'Recent Progress in the Discovery of Macrocyclic Compounds As

Obrecht, D; Robinson, J A; Bernardini, F; Bisang, C; DeMarco, S J; Moehle, K; Gombert, F O (2009). Recent progress in the discovery of macrocyclic compounds as potential anti-infective therapeutics. Current Medicinal Chemistry, 16(1):42-65. Postprint available at: http://www.zora.uzh.ch

University of Zurich Posted at the Zurich Open Repository and Archive, University of Zurich. Zurich Open Repository and Archive http://www.zora.uzh.ch

Originally published at: Current Medicinal Chemistry 2009, 16(1):42-65. Winterthurerstr. 190 CH-8057 Zurich http://www.zora.uzh.ch

Year: 2009

Recent progress in the discovery of macrocyclic compounds as potential anti-infective therapeutics

Obrecht, D; Robinson, J A; Bernardini, F; Bisang, C; DeMarco, S J; Moehle, K; Gombert, F O

Posted at the Zurich Open Repository and Archive, University of Zurich. http://www.zora.uzh.ch

Originally published at: Current Medicinal Chemistry 2009, 16(1):42-65. Recent progress in the discovery of macrocyclic compounds as potential anti-infective therapeutics

Abstract

Novel therapeutic strategies are urgently needed for the treatment of serious diseases caused by viral, bacterial and parasitic infections, because currently used drugs are facing the problem of rapidly emerging resistance. There is also an urgent need for agents that act on novel pathogen-specific targets, in order to expand the repertoire of possible therapies. The high throughput screening of diverse small molecule compound libraries has provided only a limited number of new lead series, and the number of compounds acting on novel targets is even smaller. Natural product screening has traditionally been very successful in the anti-infective area. Several successful drugs on the market as well as other compounds in clinical development are derived from natural products. Amongst these, many are macrocyclic compounds in the 1-2 kDa size range. This review will describe recent advances and novel drug discovery approaches in the anti-infective area, focusing on synthetic and natural macrocyclic compounds for which in vivo proof of concept has been established. The review will also highlight the Protein Epitope Mimetics (PEM) technology as a novel tool in the drug discovery process. Here the structures of naturally occurring antimicrobial and antiviral peptides and proteins are used as starting points to generate novel macrocyclic mimetics, which can be produced and optimized efficiently by combinatorial synthetic methods. Several recent examples highlight the great potential of the PEM approach in the discovery of new anti-infective agents. 1

Recent Progress in the Discovery of Macrocyclic Compounds as Potential Anti- infective Therapeutics

Daniel Obrecht1, John A. Robinson2, Francesca Bernardini1, Christian Bisang1,

Steven J. DeMarco1, Kerstin Moehle2, Frank O. Gombert1

1) Polyphor Ltd, Hegenheimermattweg 125, CH-4123 Allschwil (Switzerland)

e-mail: [email protected]

2) Institute of Organic Chemistry, University of Zurich, Winterthurerstrasse 190,

CH-8057 Zürich; e-mail: [email protected]

Abstract:

Several successful drugs on the market as well as other compounds in clinical development are derived from natural products. Amongst these, many are macrocyclic compounds in the 1-2 kDa size range. This review will describe recent advances and novel drug discovery approaches in the anti-infective area, focusing on synthetic and natural macrocyclic compounds for which in vivo proof of concept has been established. The review will also highlight the Protein Epitope Mimetics (PEM) technology as a novel tool in the drug discovery process. Here the structures of naturally occurring antimicrobial and antiviral peptides and proteins are used as starting points to generate novel macrocyclic mimetics, which can be produced and optimized efficiently by combinatorial synthetic methods. Several recent examples highlight the great potential of the PEM approach in the discovery of new anti- infective agents.

1. Introduction

Today, infectious diseases are the second major cause of death worldwide and the third leading cause of mortality in developed countries.[1] Due to the ability of bacteria, fungi, viruses and other pathogens to rapidly generate resistance towards established anti-infective drugs, there is increasing pressure on the pharmaceutical industry to come up with new lead compounds. Despite tremendous advances in early drug discovery technologies (e.g. combinatorial chemistry, genomics, and high throughput screening (HTS)), it has proven difficult to identify new anti-infective drugs. Most new compounds entering clinical development are follow-on compounds based on well-established drug classes. Compounds acting on novel pathogen- specific target mechanisms are scarse. Hence, there is an urgent need to discover new anti-infective drugs with novel modes of action.[2, 3]

Natural products have played a crucial role in the development of novel anti- infective drugs.[3] Amongst natural products, macrocyclic compounds clearly stand out. They often display remarkable biological activities and many of them (or their derivatives) have been successfully developed into drugs.[4, 5] The chemical diversity of macrocyclic natural products is immense and provides an invaluable source of inspiration for innovative drug design. Macrocyclic natural products generally exhibit semi-rigid backbone conformations, which place appended substituents in well-defined positions in space. Certain ring sizes are preferred.

Sixteen membered rings, for example, are found frequently in oxygen-containing macrocycles, such as many polyketides.[4, 6] In cyclopeptides, ring sizes of 3n (n being the number of amino acids in the cycle) are observed most frequently (for n= 7,

8, 11).[4] It seems that semi-rigid scaffolds may possess some of the favorable binding properties of rigid molecules (entropy), and yet are still flexible enough to adapt their conformations during a binding event (induced fit). 4

Here we review the status of macrocyclic natural products, semi-synthetic analogues and novel fully synthetic macrocylic products in anti-infective research and development. The main focus will be on compounds that are in clinical development and research compounds with proven in vivo efficacy. The compound classes include cyclic macrolactones (excluding the well known macrolide antibiotics[7]), cyclic macrolactams, cyclic depsipeptides, cyclic peptides and cyclic polyamines. Finally, we will highlight a novel approach in drug discovery: the Protein Epitope Mimetic

(PEM) technology[8, 9] and two programs that have resulted in interesting novel compounds in the anti-infective area.[10, 11]

2. Macrocyclic antibacterials

2.1 Introduction

Increasing resistance of bacteria to currently available antibiotic treatments is an emerging public health crisis.[12] Two million patients acquire infections in hospital settings (nosocomial infections) in the U.S. alone, and of these 90’000 die each year.[1-3] Furthermore, some strains of resistant bacteria are no longer confined to hospital and are now becoming prevalent in the community across the U.S. and other countries.[13] In early 2006, the Infectious Diseases Society of America (IDSA) released a “hit list” of the six top priority, most dangerous drug-resistant microbes.[14]

Among the Gram-positive bacteria, the most problematic are methicillin-resistant

Staphylococcus aureus (MRSA), Staphylococcus epidermidis, vancomycin-resistant

Enterococcus faecium and Enterococcus faecalis. A growing unmet medical need is represented by Gram-negative bacteria such as Pseudomonas aeruginosa.

Increasingly alarming is the fact that 60% of the nosocomial pneumonias are caused by Gram-negative bacteria including P. aeruginosa (17%), Enterobacter species

(17%), Klebsiella species (7%), E. coli (6%), H. influenzae (6%), and Serratia 5 marcescens (5%),[2] since success in finding new antibiotic leads against these organisms has been especially scarse. The incidences of hospital-acquired pneumonia caused by P. aeruginosa have nearly doubled from 9.6% in 1975 to

18.1% in 2003.[3] Nowadays, novel approaches are particularly needed to treat resistant strains of Pseudomonas aeruginosa, Klebsiella pneumoniae,

Stenotrophomonas maltophilia and Acinetobacter baumannii. Extended spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria have also compromised the utility of many front-line beta-lactam drugs.[13] The scarcity of suitable new compounds is causing a revival in the use of “old” antibiotics like colistin, despite concerns about well-known toxicology problems.[15]

2.2. Thiopeptide antibiotics

The thiopeptide family of natural product antibiotics consist of ~80 compounds, and many of them have been known for over 50 years.[16, 17] Thiostrepton possesses antibiotic activity against MRSA and vancomycin-resistant Enterococcus faecalis

(VREF), as well as cytotoxic activity against a number of cancer cell-lines.[18] Most of the thiopeptide antibiotics inhibit protein synthesis in bacteria by binding to a cleft located between helices 43 and 44 of the 23S-rRNA and the ribosomal protein L11, thus inhibiting binding of the GTP-dependent translation factor to the ribosome.[19]

Some inhibit directly the GTP-dependent elongation factors, e.g. GE2270A[20]

(Figure 1). A crystal structure has been determined of GE2270A in a complex with elongation factor EF-Tu,[21] revealing the conformation of the bound antibiotic and the mode of interaction with its protein receptor (Figure-1).

< Figure-1 >

Despite its high potency against some Gram-positive bacteria, including MRSA, the extremely low solubility of GE2270A has hampered its development. Using an integrated combinatorial and medicinal chemistry program, researchers at Vicuron discovered analogues of GE2270A with more favorable physico-chemical properties.[22] The total syntheses of six members of the class have been reported, including those of thiostrepton,[23] promothiocin A, amythiamicin D,[24]

GE2270A,[25] GE2270T,[26] and siomycin A.

2.3. Lysobactin/Katanosin

Lysobactin[3, 27] was first isolated by scientists at Squibb from the fermentation broth of Lysobacter sp. SC-14076 (ATCC 53042).[28, 29] Independently, scientists from

Shionogi discovered Katanosin A and B from a soil bacterium related to the genus

Cytophaga (producer strain PBJ-5356) (Figure 2).[30] Katanosin B turned out to be identical to lysobactin. Bacterial cell wall biosynthesis is the primary target of these antibiotics, however, the mechanism of action is different from that of vancomycin.[31-33] The lysobactins are cyclic depsipetides containing several non- proteinogenic D and L amino acids. In particular, four β-hydroxylated amino acids seem to be responsible for the remarkable hydrolytic stability of the amide bonds. On the other hand, the lactone bond in lysobactin is prone to hydrolysis.[34] However, its stable and highly potent amide analogue has been prepared.[35] The total syntheses of lysobactins have recently been highlighted.[27]

< Figure-2 >

The crystal structure of lysobactin is characterized by a constrained cyclic peptide backbone stabilized by multiple intramolecular hydrogen bonds.[31] The two N- 7 terminal leucine moieties are also involved in tight hydrogen bond and van der Waals contacts with the backbone (Figure-2). Lysobactin and katanosin A are highly active against Gram-positive bacteria, with significant activity against methicillin-resistant

MRSA as well as vancomycin-resistant enterococci (VRE). In these pathogens sub- micromolar MIC values are obtained, clearly superior to that of vancomycin. The high in vivo efficacy was confirmed in a systemic murine S. aureus infection model (ED50

1.8 µg/kg i.v., CFU 105).[3]

2.4. Glycopeptide antibiotics: dalbavancin, oritavancin and telavancin

Vancomycin, introduced in 1959, and teicoplanin, are the two glycopeptides antibiotics that have been in clinical use for many years.[3, 36-39] They are regarded as the antibiotics of last resort against resistant staphylococci and enterococci,[36]

However, the emergence of resistant strains has spurred on the search for active analogues of both vancomycin and teicoplanin.

Glycopeptides are active against most Gram-positive bacteria and a few anaerobic organisms such as Clostridium difficile. Vancomycin is bactericidal (except against enterococci) and acts by complexing the D-alanyl-D-alanine portion of peptide precursors in peptidoglycan biosynthesis, thus inhibiting peptidoglycan transpeptidase and transglycosylase reactions.

Despite some tremendous achievements in the total synthesis of glycopeptides antibiotics[40, 41] new analogues are generally obtained by semi- synthesis from precursors (vancomycin, teicoplanin) produced by fermentation.

Among the numerous glycopeptide analogues that were synthesized and clinically evaluated, dalbavancin (Versicor-Pfizer),[42] oritavancin (Lilly-Targanta)[43] and telavancin (Theravance-Astellas)[44] (Figure 3) are the most advanced.[45-47]

< Figure-3 >

Dalbavancin exhibits an unusually long half-life (6-10 days) owing to high protein binding and hence can be administered once weekly.[48] From their pharmacokinetic and pharmacodynamic properties, oritavancin and telavancin seem to be the most promising vancomycin successors.

2.5. Daptomycin

Daptomycin (LY146032; Figure 4) is derived from A21978C lipopeptide factor C1, one of the fermentation products of Streptomyces roseoporus.[49, 50] Daptomycin belongs to the lipopetide family of antibiotics and consists of a 31-membered cyclodepsipeptide core and a tripeptide side-chain, which is acylated with a lipophilic group at its N-terminus. It was approved in 2003 for complicated skin and skin structure infections (cSSSI) and in 2006 for the treatment of blood stream infections.[51] It is active against S. aureus, coagulase-negative staphylococci, enterococci and streptococci. Daptomycin is rapidly bactericidal (less than one hour) and acts by bacterial membrane depolarization and disruption, which results in inhibition of macromolecular synthesis. It has a high protein binding (91-96%) and its activity is Ca2+ dependent.[51] Variations of the daptomycin structure revealed that two of the four aspartic acid residues are essential for activity.[38, 52, 53]

< Figure-4 >

2.6. Ramoplanin and AC 98-6446

Ramoplanin A2 is one the structurally most complex lipodepsipeptide antibiotics and exhibits extraordinary antibacterial activity against Gram-positive bacteria,[54, 55] in particular, against drug-resistant Enterococcus faecium and MRSA. The ramoplanins 9 are produced by Actinoplanes ATCC 33076 and consist of a 49-membered ring composed of 17 amino acids (Figure 5), in which 12 of them possess unusual side- chains and seven possess a D-configuration.[56] The 3D structure of ramoplanin established by NMR is characterized by two antiparallel beta-strands formed by residues 2-7 and 10-14, respectively, which are connected by a reverse beta-turn with Thr-8 at position i+1 and Phe-9 at position i+2.[57] The U-shaped conformation appears to be stabilized by a hydrophobic cluster of aromatic side chains from residues 3, 9 and 17.

< Figure-5 >

Ramoplanins inhibit bacterial peptidoglycan biosynthesis by binding to lipid

II.[58] As a result, bacteria produce a weakened cell wall, which is sensitive to lysis.

Several clinical studies have shown the utility of ramoplanin A2 in suppressing enterococcal infections and oral treatment of Clostridium difficile-associated diarrhea in the gastrointestinal tract in the nares (ointment). The molecule has been fast- tracked by the US FDA for these indications.[54] Related to the ramoplanins are enduracidin A and B.

A semisynthetic mannopeptomycin AC 98-6446 (Figure 6) has been shown to have potent in vitro activity against a large number of resistant and sensitive staphylococci, enterococci and streptococci.[59]

< Figure-6 >

2.7. WAP-8294A2

WAP-8294A2 (Figure 7) is a 40-membered cyclic depsipeptide containing 12 amino acids (7 with (R)-configuration) and one β-hydroxy acid. It was isolated from a Gram- negative Lysobacter sp. in Japan.[60-62] WAP-8294A2 shows strong in vitro activity against Gram-positive bacteria including methicillin-resistant S. aureus (MRSA; MIC:

0.49µM) and vancomycin-resistant enterococci (VRE; MIC: 3.93 µM) and is also highly active in vivo. The activity is increased in the presence of human serum and is

14 times higher than vancomycin in a similar setting. WAP-8294A2 seems to damage the bacterial cell membrane by binding to phospholipids. WAP-8294A2 is expected to be clinically useful as a parenteral (i.v.) anti-MRSA agent.

< Figure-7 >

2.8. Streptogramins

Streptogramin antibiotics (Figure 8) are produced as secondary metabolites by a number of Streptomyces species and occur as synergistic mixtures of Group A (or M; polyunsaturated macrolactones) and Group B (or S; cyclic hexadepsipeptides) compounds.[37, 63, 64] The streptogramin family of antibiotics includes the mikamycins, pristinamycins, ostreomycins and virginiamycins. The first streptogramin antibiotic, pristinamycin (Figure 8), produced in Streptomyces pristinaespiralis, was developed in France more than 35 years ago and has been primarily used for the treatment of respiratory and skin structure infections.[65]

< Figure-8 >

Pristinamycin consists of a variable mixture of pristinamycin Ia (24-38%) and pristinamycin IIa (54-68%) and is hardly water-soluble. Quinopristin/dalfopristin

(30/70; Figure 9) was developed as a water-soluble derivative of pristinamycin with a selective spectrum against Gram-positive organisms. The synergistic quinupristin/dalfopristin mixture became available in the United States in 1999 for the treatment of infections caused by vancomycin-resistant Enterococcus faecium and those caused by other Gram-positive pathogens for which the other available agents are ineffective or not tolerated. The target of quinupristin and dalfopristin is the bacterial ribosome.

< Figure-9 >

Dalfopristin blocks an early step of protein synthesis (elongation) whereas quinupristin blocks a subsequent step by inhibiting peptide synthesis. The effect of both drugs is thus inhibition of protein synthesis. [37] Crystal structures of quinuprisitin and dalfopristin bound to bacterial 50S ribosomal subunits have been reported (Figure 9).[66, 67]

2.9. Biphenomycins

Biphenomycin A (WS-43708A) was reported by scientists from Fujisawa in 1985[3,

68] and was found to be identical with LL-AF283a isolated from S. filipinensis at the

Lederle Laboratories in 1967.[69] A major discrepancy was noted between the in vitro and in vivo activity of biphenomycin (Figure 10). Administered subcutaneously along with S. aureus (ED50= 1 mg/kg) the compound was five-times more effective than vancomycin in a mouse septicemia experiment.[70] In vitro, however, the compound was virtually ineffective up to 200 µg/ml. 12

< Figure-10 >

The synthesis of biphenomycin B was described in 1991 and opened up the possibility of producing more potent analogues.[71] A close analogue of biphenomycin B (Figure 10) showed an improved spectrum of activity in vitro. In particular, C-terminal amide derivatives showed improved in vitro activity and excellent in vivo efficacy.[72] Bacterial protein biosynthesis seems to be the target of this novel class of antibacterials.[3]

2.10. Tuberactinomycins and Capreomycins

The tuberactinomycin and capreomycin antibiotics (Figure 11) are cyclic pentapeptide natural product antibiotics.[3] Viomycin (tuberactinomycin B), discovered in 1951,[73] was marketed by Ciba and Pfizer as a tuberculostatic agent in the 1960s. The capreomycins were isolated from Streptomyces capreolus.[74-76]

< Figure-11 >

The tuberactinomycins and capreomycins show good activity against

Mycobacteria including multi-resistant strains, however, only very limited activity against other bacteria. Intense efforts have been made to generate synthetic modifications of these interesting antibiotics, with the aim of broadening the antibacterial spectrum.[3] Finally, by using de novo synthesis, scientists from Pfizer obtained compounds with significantly enlarged antibacterial spectrum (Figure

12).[77-79]

< Figure-12 >

2.11. Enopeptins

The enopeptins and closely related A54556 A and B (Figure 13) are 16-membered cyclic depsipeptides. The latter were described by researchers from Eli Lilly[80] in

1985 and enopeptins A and B were isolated in 1991 from a culture broth of

Streptomyces sp. RK-1051 in Japan.[81] Enopeptins are active against Gram- positive and some Gram-negative membrane defective bacterial mutants. A total synthesis was described in 1997.[82] Researchers at Bayer have revised the initial structure of A54556A,[83] and have determined the mechanism of action.[84] The conformation has also been studied by NMR in DMSO solution.[85]

< Figure-13 >

The Bayer researchers identified casein lytic protease (ClpP) as the molecular target of these interesting antibiotics. Bayer initiated an optimization program around

A54556 A and B in order to enlarge their in vitro spectrum, improve their ADME properties,[86] and to achieve in vivo activity. Extensive optimization resulted in potent synthetic analogues. A selected example is shown in Figure 14, which exhibited the following MICs (µg/ml): S. aureus (0.5); S. pneumoniae (≤0.125); E. faecium (≤0.125); E. faecalis (≤0.125).[3] In this project, efficient de novo synthesis rather than a fermentative/semisynthetic approach has been used to systemically explore the potential of the natural-product lead structures.

< Figure-14 >

2.12. Antimicrobial macrocyclic peptides

Antimicrobial and host-defense peptides are important components of the innate immune defenses of all organisms.[87, 88] Cationic antimicrobial peptides possess significant activities against Gram-negative and Gram-positive bacteria, fungi, enveloped viruses and parasites.[89] These peptides can be linear or cyclic, and show a variety of secondary structures, including β-sheet, α-helical, extended and β- turn structures. The compounds generally exhibit an amphipathic structure with a hydrophobic and a hydrophilic (cationic) face. The antimicrobial peptides target in general the bacterial membrane, however, in many cases they also interact with mammalian cells leading to significant toxic side-effects when applied systemically.

For this reason, the application of antimicrobial peptides in the clinic has so far been limited to topical use. Nevertheless, antimicrobial peptides have generated a lot of interest as starting points for the development of new antibiotics, also due to the considerably low incidence of resistance. Among the macrocyclic antimicrobial peptides gramicidin S, tyrocidine, polymyxin B, protegrin I and its synthetic analogue

IB-367 (iseganan) are perhaps the best known.[87]

Tyrocidine A

Tyrocidine A (Figure 15) belongs to a large class of peptide antibiotics related to gramicidin S, both of which were isolated from Bacillus subtilis. These antibiotics all contain a cyclic decapeptide core. Tyrothricin, a close analogue of tyrocidine A, has been used for topical treatment of Gram-positive bacterial infections, and like gramicidin S, is essentially limited to topical applications due to nephrotoxicity[90].

The molecule adopts a β-type amphipathic structure, which is the cause for the membranolytic mechanism of action.[91]

< Figure-15 >

Tyrocidine A associates preferentially with the bacterial outer cell wall, which is predominantly negatively charged, as opposed to the neutral membranes more commonly found in eukaryotes.[92] Approaches to improve the biological activity and the therapeutic index (as defined by the ratio of MHC/MIC; MHC, minimal hemolytic concentration) have been described.[92-95]

Polymyxins (Colistin)

Polymyxins were isolated in 1947 from different strains of Bacillus polymyxa.[15, 96,

97] Polymyxins are highly active against a broad panel of Gram-negative bacteria, including Pseudomonas aeruginosa and Acinetobacter baumannii. Early administration of these antibiotics is associated with several reports of adverse renal and neurological effects in a large number of patients.[98, 99] Thus, compounds in this class of antibiotics were gradually withdrawn from clinical practice and replaced by newer antibiotics with the same or a broader spectrum, but were retained for the potential treatment of cystic fibrosis (CF) patients in combination with tobramycin.

The emergence of Gram-negative bacteria that are resistant to all classes of available antibiotics except polymyxins, especially Pseudomonas aeruginosa and

Acinetobacter baumannii strains, have led recently to a renaissance in their clinical use.[15] In particular, the previously reported toxicity of polymyxins has been carefully re-evaluated in the context of new dosing regimens.[100]

< Figure-16 >

The family of polymyxins consists of five compounds, polymyxin A, B, C, D, and E (colistin), whereby only B and E have been used clinically. Colistin may contain different amounts of polymyxin A and B (see Figure 16), and is commercialized in two forms. Colistin sulfate is used orally for bowel decontamination and topically as a powder for skin infections, and as colistimethate sodium, which is applied parenterally and by inhalation. The prodrug colistimethate sodium is less active than the parent drug colistin, however, it is also less toxic. Toxicity is generally associated with the highly cationic, amphiphilic and thus hemolytic nature of the polymyxins.

Polymyxin B sulfate is used parenterally, topically (ophthalmic and otic instillation), intrathecally, and by inhalation.[15] Several attemps have been made over the past years to find polymyxin analogues with a more favorable therapeutic index. For instance, acylation of Dab-9 with arginine results in a compound with an increased therapeutic window in vivo (LD50/PD50=60).[101]

Protegrin 1 and IB-367

Protegrin-1 (PG-1) is a cysteine-rich, 18-residue β-hairpin peptide isolated from porcine leukocytes and shows antimicrobial activity against a broad range of microorganisms (Figure 17).[102] The MICs of PG-1 against representative Gram- negative and Gram-positive bacteria ranged from 0.12-2 µg/ml. At these levels PG-1 is rapidly bactericidal in vitro, reducing the number of CFUs of either methicillin- resistant MRSA or Pseudomonas aeruginosa by more than three log units in less than 16 minutes. Immunocompetent mice inoculated intraperitonealy (i.p.) with P. aeruginosa or S. aureus exhibited 97-100% mortality in the vehicle control group compared with 0-27% mortality in animals that received a single i.p. injection of PG-1

(0.5mg/kg).[102] IB-367, a close relative of PG-1, was developed as an oral rinse 17 solution for the potential prevention of ventilator-associated pneumonia but failed in

Phase III clinical development due to efficacy and toxicity problems.

< Figure-17 >

The structure of protegrin I has been studied in solution and in membrane mimicking environments, where it adopts a ß-hairpin structure.[103-105] In a membrane environment the hairpin has also been detected as a dimer (PDB

1ZY6).[106, 107]

3. Macrocyclic antivirals

3.1. Introduction

High-throughput screening of small molecule libraries has been more successful in discovering good leads in the antiviral than in the antibacterial area.[108] However, so far these leads hit only a limited number of targets. Well established targets include those involved in viral replication, including RNA-dependent DNA polymerase or reverse transcriptase for HIV, RNA-dependent RNA polymerase or RNA replicase for HCV, and viral proteases (aspartyl proteases for HIV and serine proteases for

HCV).[109] More recent targets include inhibition of viral entry. Binding of HIV to

CD4+ cells requires successive non-specific interactions with cell surface heparan sulphates, followed by specific binding to the CD4 receptor and the CXCR4 and/or

CCR5 co-receptor, before the cell fusion process can occur. The binding of HCV to the cell surface and its entry into cells may involve the low-density lipoprotein receptor (LDLR), glycosaminoglycans (GAG), scavenger receptor class B (SR-BI, also known as SCARB1), among other events. Furthermore, HIV integrase, inhibition 18 of HIV maturation, and HIV and HCV cyclophilin inhibition have emerged as viable targets in the anti-viral field.

Natural product screening has been a valuable source for novel antiviral lead compounds. Among the macrocyclic products that are in clinical development as anti-

HCV compounds are ciluprevir[110] and ITM-191,[111] which inhibit the HCV NS3 viral protease. In addition, Debio-025,[112] an inhibitor of cyclophilin, is an analogue of cyclosporin A lacking the immunosuppressive activity, and has emerged as an attractive candidate for the treatment of HCV. In the area of HIV inhibitors, the cyclic polyamine AMD3100,[113] callipeltin A[114] and a series of novel PEM-based

CXCR4 antagonists with potent anti-HIV activity have emerged.[10] Furthermore, detruxin B [115] with activity against HBV constitutes another promising macrocyclic lead structure.

3.2. Macrocyclic lead compounds for treatment of HCV

BILN 2061 and ITMN-191

HCV infection afflicts an estimated 170 million people world-wide. End-stage liver disease and liver failure resulting from HCV infection are currently the major causes of liver transplantation in the US and Europe.[109, 116] HCV is a small, enveloped single-stranded RNA virus. Current therapy involves application of pegylated interferons in combination with the broad-spectrum nucleoside analogue ribavirin.

The fully synthetic, orally available macrolactams BILN 2061 (cilepruvir)[110,

116, 117] and ITMN-191 (Figure 18),[111] which potently inhibit the HCV encoded

NS3 protease, have recently emerged as potentially interesting new therapeutics for

HCV (Figure 18). As the NS3 protease plays a critical role in the maturation of the viral polyprotein precursor, it was recognized early on as a potential target for antiviral development.[115] BILN 2061 and ITMN-191 are reversible inhibitors of the 19 serine protease NS3 of HCV. Capitalizing on knowledge from known N-terminal linear hexa- and tetrapeptide cleavage products, which are potent inhibitors of the protease, BILN 2061 was obtained after several rounds of optimization.[110, 117] In particular, vinyl-ACCA was found as a potent replacement of cysteine at the P1 position, and macrocyclization improved the ADME properties significantly.

< Figure-18 >

Ciluprevir inhibits the HCV NS3 protease in both in vitro enzymatic (IC50= 3 nM) and cell-based replicon assays (EC50= 1.2nM). The compound shows good oral bioavailability in rats (F=42%) with low plasma clearance. A 2-day, twice-daily administration of ciluprevir to patients infected with HCV genotype 1 resulted in an impressive reduction of HCV RNA plasma levels (~3 log reduction) and provided the proof-of-concept in man. In recent toxicological studies in animals receiving high doses of ciluprevir for 4 weeks, cardiac toxicity was observed. As a result, clinical trials were put on hold. Modifications of the carboxylate group, e.g. into sulfonimides such as in ITMN-191,[111, 116] led to macrocyclic compounds with improved toxicity profile.[116]

Debio-025

More than a decade ago, cyclophilin A (Cyp A) was recognized as a target for the anti-HIV activity of cyclosporin A and non-immunosuppressive analogues such as

Debio-025 (Figure 19).[109, 112] Cyp A binds specifically to the HIV-1 gag protein[118] and was also reported as a functional regulator of the HCV NS5B RNA replicase.[119] Debio-25 has strong inhibitory activity on HCV replication without exhibiting the immunosuppressive effect of cyclosporin A.[120] 20

< Figure-19 >

3.3. Macrocyclic lead compounds for treatment of HIV

AMD3100 and related cyclic polyamines

Binding of HIV to CD4+ cells requires successive non-specific interactions with cell surface heparan sulfates, followed by specific binding to the CD4 receptor and the

CXCR4 and/or CCR5 co-receptor, before the cell fusion process can occur.[109]

Fusion inhibitors for M-tropic HIV viruses to CCR5 and T-tropic viruses to CXCR4 have become a focus in the search for novel anti-HIV therapies.[121] Among the macrocyclic lead compounds that inhibit CXCR4, the family of bicyclams such as

AMD3100 and AMD 3465 (Figure 20) have emerged as first leads.[122]

< Figure-20 >

AMD3100 shows potent activity against several strains of HIV-1 in the 1-10 ng/ml range, but it has to be administered by subcutaneous injection. In an open label dose-escalating phase I/II trial in HIV patients, one patient with pure X4 virus exhibited a clear viral load reduction.[123] However, AMD3100 induced cardiac adverse effects and the clinical development for HIV was discontinued. As an alternative, AMD3100 is currently being developed for stem cell mobilization in combination therapy with G-CSF.[121]

Callipeltin A

The 22-membered cyclic depsipeptide callipeltin A (Figure 21) and its congeners isolated from the marine sponge Callipelta sp. from New Caledonia exhibit potent 21 antifungal and anti-HIV activities.[55, 114] More recently, callipeltins A-C were isolated from the marine sponge Latrunculia sp. from Venatu Islands.[124] The identification of the three unusual amino acids was achieved by synthesis.[125] The most relevant biological activity of callipeltins is their anti-HIV effect, clearly demonstrated in their action against CEM4 lymphocytic cells infected with HIV-1 (Lai strain; EC50= 6.6 nM).[114, 126] However, callipeltin A is also quite cytotoxic

(EC50=0.19 µM).

< Figure-21 >

In addition to its anti-HIV activity, callipeltin A was found to have a positive ionotropic effect as a powerful inhibitor of the Na+/Ca2+ exchanger in guinea pig left atria.[127] Related to the callipeltins and the papuamides, neamphamide A a cyclic depsipeptide with potent anti-HIV activity was recently described.[128] Despite the relatively low therapeutic window, the callipeltins may serve as good starting points for the design of analogues with more favorable ADMET properties.

4. Macrocyclic antifungals

4.1. Introduction

Fungi have emerged world-wide as an increasingly frequent cause of health-care associated infections.[129, 130] Whereas superficial fungal infections of the skin and nails can be treated successfully, the incidents of serious fungal infections are becoming an increasing concern.[131, 132] The key pathogens are Candida albicans, azole-resistent C. albicans, C. glabrata, C. krusei, C. parapsilosis,

Aspergillus fumigatus and Cryptococcus neoformans.[130] Among the invasive fungal infections, Candida accounts for 70-90% and Aspergillus for 10-20% of the 22 cases. A rise in life-threatening systemic fungal infections has been reported in HIV patients who generally suffer from a compromised immune system.

Beside the standard treatment with the fungicidal (and toxic) polyene amphotericin B, and the fungistatic (but safer) azoles such as fluconazole and itraconazole, the family of echinocandins[133] has successfully entered the market.

Both amphotericin B and the echinocandins are derived from macrocyclic natural products. A water-soluble macrocyclic polyene derivative SPK-843[134, 135] entered phase II clinical trials for systemic mycosis in November 2004 and its efficacy in candidiasis was superior to that of amphotericin B (see also next paragraph).

4.2. Amphotericin B

Synthetic and semi-synthetic polyene macrolactone antifungals bind primarily to ergosterol, resulting in alterations in membrane permeability and leading ultimately to cell death.[129] Used since 1950, amphotericin B (Figure 22) is considered to be the gold standard for therapy of numerous serious invasive fungal infections.[136, 137]

Amphotericin B is fungicidal and exhibits a broad spectrum activity against serious invasive pathogens like candida, aspergillus and cryptococci.

< Figure-22 >

Amphotericin B is used clinically as a deoxycholate, lipid complex, colloidal dispersion, and as a liposomal formulation.[136] This formulation was efficacious in the treatment of invasive aspergillus [138] and its renal safety was proven in 106 patients with cryptococcal infection.[139] A water-soluble macrocyclic polyene derivative SPK-843 entered phase II clinical trials for systemic mycosis in November

2004, and its efficacy in candidiasis was superior to that of amphotericin B. 23

4.3. Echinocandins

The echinocandins, first discovered in 1974 (Figure 23), are a growing family of cyclic lipopeptide antifungal natural products.[140] They are macrocyclic hexapeptides containing a labile hemiaminal moiety and fatty acid that is N-linked to the peptide core. Furthermore, they are composed of four β-hydroxylated non-natural amino acids, including 3-hydroxylated and 4-hydroxylated proline residues. The echinocandins have been synthetically modified after extraction from the fermentation broths of various fungi.[129] Caspofungin is derived from Glarea lozoyenisi, micafungin from Coleophoma empedri, and anidulafungin from Aspergillus nidulans.

Recently, a semi-synthetic three step synthesis of caspofungin from pneumocandin

Bo has been described.[141] Echinocandins act mechanistically at the level of cell wall β-1,3-glucan synthesis by inhibition of β-1,3-glucan synthase.[142] This inhibition results in osmotic lysis of the cell leading to fungicidal activity against Candida sp.[143, 144]

< Figure-23 >

These agents show a broad-spectrum activity and resemble each other with respect to in vitro activity against Candida sp., with micafungin and anidulafungin showing generally lower MICs than caspofungin.

Caspofungin, micafungin, and anidulafungin are relatively safe and effective agents for the parenteral (i.v.) treatment of candida infections[133] and constitute valuable alternatives to azoles and polyenes for the treatment of serious invasive infections and have been approved by the US FDA.

4.4. Aureobasidin

Aureobasidin A (basifungin, LY295337) belongs to a family of cyclic depsipeptide antifungals and is produced by Aureobasidium pullulans.[130, 145] Aureobasidin

(Figure 24) contains two (S)-N-methyl valines, one (S)-N-methyl phenylalanine and a

(S)-N-methyl-β-hydroxy valine, which is crucial for the antifungal activity.

Modifications to amino acids at positions 6, 7 and 8, with the aim of improving the activity were attempted with limited success.[146]

< Figure-24 >

Aureobasidin A is a substrate for ABC transporters,[147] such as the multi-drug resistance (MDR) subgroup, and competitively inhibits efflux of other substrates.

Furthermore, it lacks activity on Aspergillus fumigatus. Nevertheless, aureobasidin A constitutes an interesting lead structure, which seems worthwhile to pursue.

4.5. UK2A and UK3A

A family of cyclic nine-membered dilactone natural products, including antimycin,

UK2A and UK3A (Figure 25) have been isolated from Streptomyces sp. 517-02.[130,

148-150] The three compounds show broad spectrum antifungal activity against C. albicans and Aspergillus spp. UK2A and UK3A are devoid of any antibacterial activity, as seen in antimycin, which is also quite cytotoxic.

< Figure-25 >

In contrast to UK2A and UK3A, antimycin seems to rapidly stimulate intracellular production of reactive oxygen species.[151] The main mechanism of action for UK2A 25 and UK3A, however, is inhibition of mitochondrial electron transport and interference with in vitro respiration in both yeast and rat mitochondria. Hence, these compounds could be valuable lead structures for the design of drugs that target fungal respiration.

4.6. Pseudomycins

The pseudomycins (Figure 26)[55, 152, 153] are produced in large amounts by

Pseudomonas syringae MSU 16H[154] and represent a new class of antifungal metabolites active against a broad range of plant pathogenic fungi, as well as

Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. The family comprises also the potent anthelmintic compounds PF1022 described in chapter 5.

< Figure-26 >

5. Macrocyclic anthelmintics

5.1. Emodepside (BAY 44-4400) and PF 1022A-D

PF 1022A-D isolated from Mycella sterilia,[155] belongs to the family of pseudomycins (Figure 27; see also section 4) isolated from Pseudomonas syringae.[55] PF 1022A shows potent, broad spectrum anthelmintic activity with low toxicity.[156] After discovery of the avermectins and milbemycins, PF 1022A was seen as a prototype of a new class of anthelmintics. PF 1022A acts probably as a neurotoxin, however, the exact mechanism of action is still under investigation,.[157]

< Figure-27 >

The high potential of PF 1022A as a new anthelmintic lead compound prompted the synthesis of a large number of analogues[158] with the aim of improving the biological activity and pharmacological properties. Emodepside (BAY

44-4400), a semi-synthetic analogue of PF 1022A, is highly effective against a broad panel of intestinal and extraintestinal nematodes, and also against filarial parasites.[159]

6. Protein Epitope Mimetics (PEM) technology: A novel approach in anti- infective drug discovery

6.1. Introduction

The Protein Epitope Mimetics (PEM) approach to drug discovery is based upon the design of synthetic peptidomimetic molecules that mimic the functionally important epitopes in biologically relevant peptides and proteins, such as those based on β- hairpin and α-helix secondary structure motifs. By transferring the epitope from a recombinant to a synthetic scaffold that can be produced efficiently by parallel combinatorial methods, the chemical, biological and drug-like properties of an initial hit can be optimized through iterative rounds of library synthesis and screening.

The β-hairpin is an especially interesting scaffold, which is used by many proteins for biomolecular recognition. β-Hairpins are amenable to mimetic design, for example, by transplanting a loop sequence from the protein or peptide of interest onto a synthetic template that can act to stabilize hairpin backbone conformations

(Figure 28).[8, 10, 11] In the resulting macrocyclic peptidomimetics (or PEM molecules), additional stabilization of β-hairpin conformations may be achieved by introducing disulfide bonds between cysteine residues located at opposite, preferably non-hydrogen-bonded sites in each β-hairpin strand. The most commonly used template in the ß-hairpin PEM molecules studied so far is the dipeptide unit DPro- 27

LPro, which adopts a very stable type-II' ß-turn, and so is ideal to nucleate ß-hairpin conformations.

< Figure-28 >

β-Hairpin template-bound PEM molecules can be rapidly and efficiently produced using a mixed solid- and solution-phase parallel synthesis process.[8] An enormous potential diversity can be generated in such synthetic molecules, simply by variations in the number and types of building blocks. The diversity achievable comes close to that seen within the large family of macrocyclic peptide-based natural products (vide supra). The production of PEM molecules can be carried out in a parallel combinatorial process that gives libraries typically containing several dozen

PEM molecules. In iterative cycles of parallel PEM library synthesis and testing, initial hits can be optimized based on biological activity as well as ADMET properties. Due to their macrocyclic, conformationally constrained nature, these molecules can be endowed with excellent small molecule-like pharmacokinetic properties, which differ significantly from those of linear peptides. The 3D structures of PEM molecules both free in solution and in complexes with the target receptor were investigated by NMR and crystallography. The resulting 3D structure-activity relationships may then provide incisive SAR information that can feed back into the iterative library design and optimization process. The NMR structures of several PEM molecules, including two in complexes with their receptors, have been described earlier.[8, 11, 160-169]

6.2. Antiinfective PEM molecules

Nature has evolved remarkable mechanisms to protect animals from viral and microbiological attack, based on the innate and adaptive arms of the immune system. 28

Within the innate immune system, a first line of defense is provided by several families of peptides and proteins produced by immune cells, that possess antibacterial, antifungal and antiviral activities.[88, 170] Examples include the defensins, protegrins, cecropins, magainins, indolicidin and related cationic amphiphilic host-defense peptides. These peptides are gene-encoded, and are produced from precursor proteins through one or more proteolytic steps. Overall, their mechanisms of action are diverse and complex, ranging from a direct killing action by targeting bacterial cell membranes for disruption (e.g. the protegrins), to modulating the biological activity (gene expression, chemoattraction, differentiation, induction of cytokines and chemokines) of immune cells. These peptides, therefore, represent targets of outstanding interest for the PEM approach to drug design. PEM molecules (Figure 28) based on anti-viral natural products like polyphemusin II,[171,

172] and antimicrobial peptides such as protegrin I,[102] tachyplesin,[173] and RTD-

1,[174] represent an ideal starting point for the design of novel antibacterial and antiviral agents (Figure 29).

< Figure-29 >

6.3. Antimicrobial PEM molecules

Cationic amphiphilic antimicrobial peptides comprise a large family of compounds showing broad-spectrum antimicrobial activity against Gram-positive and Gram- negative bacteria. The main mechanism of action seems to involve lysis of the bacterial cell membrane.[175] Indeed, the strong hemolytic activity of antimicrobial peptides on typical eukaryotic (e.g. red blood) cells, has so far limited their clinical use to topical applications. 29

The first starting point for PEM design was the antimicrobial peptide protegrin I and its closely related synthetic analogue IB367 (chapter 2.12). Libraries of PEM molecules incorporating sequences related to protegrin I were synthesized and optimized, to afford compounds possessing potent broad spectrum antimicrobial activity.[11, 176] By iterative library screening it was possible to to obtain analogues such as 1 with considerably reduced hemolytic activity on red blood cells (Figure 30).

A stable hairpin conformation for 1 was observed by NMR, but only in a micelle

(membrane-like) environment.[11] SAR studies, involving the synthesis and testing of a large number of single site substituted analogues, showed that the antimicrobial activity was tolerant to a large number of the changes made.[176]

< Figure-30 >

Efforts have been made to understand the observed antimicrobial and hemolytic structure-activity relationships in terms of a QSAR model.[177] The best model suggested that the antimicrobial potency correlates with the peptide charge and amphipathicity, while the hemolytic effects correlate with the lipophilicity of residues forming the non-polar face of the ß-hairpin. Related β-hairpin mimetics have also been made with a mixed peptide-peptoid backbone (4 and 5),[168] while others contain templates based on a xanthene[11] (2) or a biaryl derivative (3).[178] Many of these molecules retain potent broad spectrum antimicrobial activity, and are potentially interesting starting points for further optimization.

More recently, a new structure-activity trail has provided access to derivatives with a much higher potency and selectively against Pseudomonas aeruginosa. These new derivatives do not cause cell lysis, and only one enantiomer retains significant potency, suggesting a different mechanism of action (to be published). One of these 30 molecules, POL7001, exhibits potent in vitro activity against a broad panel (>125 strains) of Pseudomonas strains (including multidrug-resistant clinical isolates from

CF patients) with a MIC90= 0.2 µg/ml. In addition, POL7001 showed potent activity in an in vivo septicemia mouse model against P. aeruginosa PAO1 (EC50= 0.3 mg/kg) and was 10 times more potent than gentamycin tested in the same model. Hence, these PEM molecules may constitute a novel class of antibiotics. They show great promise in the fight against multidrug resistant P. aeruginosa, and one (POL7080) is currently in preclinical development.

6.4. POL3026: A potent and specific CXCR4 inhibitor exhibiting strong anti-HIV activity

The chemokine receptor CXCR4 and its ligand CXCL12 (SDF-1α) have also emerged recently as important therapeutic targets. CXCR4 inhibitors are of great interest in hematopoetic stem cell mobilization, cancer, inflammation and HIV.

CXCR4 was first discovered as a co-receptor, with CD4, for the entry of T-tropic (X4)

HIV-1 into T-lymphocytes.[179, 180] One of the first inhibitors of CXCR4 described was the natural peptide polyphemusin II,[171, 172] and a closely related synthetic analogue T22 ([Tyr5,12, Lys7]-polyphemusin II),[181] (Figure 29). T22 exhibits a well- structured β-hairpin conformation by NMR,[182] and thus constituted a good starting point for PEM design. Several PEM libraries were synthesized and tested in iterative rounds of optimization. POL3026 (Figure 31) shows potent inhibition of CXCR4

(IC50= 1.2nM, Ca-flux assay) and good pharmacokinetic properties.[10] The high activity of POL3026 was further confirmed in several anti-HIV tests,[183] including an in vitro cell fusion assay (FIGS), virus replication assays (deCIPhR), and acute CEM cell infection assays.

< Figure-31 >

7. Summary and outlook

Macrocyclic natural products constitute the largest group of molecules among the compounds that are currently in preclinical and clinical stages in the antiinfective area. Due to their virtually unlimited diversity, natural products are also a rich source of inspiration for the development of novel lead compounds. Although many ring sizes are observed in macrocyclic natural products it is interesting to note that some ring sizes are over-represented.[4] It seems that in cyclic peptide and depsipeptide natural products, various hairpin-like and β-turn conformations are favored (vide supra).

We have also highlighted in this review the Protein Epitope Mimetics (PEM) technology, which constitutes a new approach in drug discovery. PEM molecules can mimic the β-hairpin and α-helical secondary structure elements often observed in protein-protein interactions. POL7080 and POL6326 were derived from the β-hairpin- shaped natural peptides protegrin I and polyphemusin II. In rapid iterative cycles including design, synthesis, purification and biological profiling, optimized PEM molecules could be obtained with greatly improved ADMET properties compared to the starting natural products. The PEM approach thus efficiently generates fully synthetic compounds with drug-like properties, which display natural product-like structural complexity. While the anti-Pseudomonas compound POL7080 has moved into preclinical toxicological studies, POL6326 has successfully completed Phase I clinical studies for stem cell mobilization.

Figures and Legends

Figure 1. Thiopeptide antibiotic GE2270A. Right, crystal structure of GE2270A bound to EF-Tu. The spheres indicate the hydrogen bond acceptors with the EF-Tu binding site (PDB 2C77).

Figure 2. Structures of lysobactin and katanosin A. Right, the crystal structure of lysobactin (Cambridge Crystal Database CCDC_623590).

Figure 3. Structures of dalbavancin, oritavancin and telavancin; and the crystal structure of vancomycin (PDB 1SHO).[184]

Figure 4. Molecular formula and NMR structure of daptomycin (PDB 1XT7).[185]

Figure 5. Molecular formula and NMR average solution structure (PDB 1DSR) of ramoplanin A2.

Figure 6. Structure of AC 98-6446.

Figure 7. Structure of WAP-8294A2.

Figure 8. Structures of pristinamycin IA and IIA.

Figure 9. Quinupristin and dalfopristin. bottom left, crystal structure of quinupristin

(PDB 1YJW) bound to the large ribosomal subunit.[66] The overall conformation is cup-shaped, with the phenyl and pyrrolidine rings stacked on each other at the 34 bottom of the cup. bottom right, crystal structure of dalfopristin also bound to a bacterial large ribosomal subunit (PDB 1sm1).[67]

Figure 10. Structures of biphenomycins.

Figure 11. Structures of tuberactinomycins and capreomycins.

Figure 12. Structure of a synthetic analogue of the tuberactinomycins.[79, 186]

Figure 13. Structures of ennopeptin A and B, A54556-A and A54556-B, and the average solution conformation of enopeptin A by NMR.[85]

Figure 14. Structure of a synthetic analogue of the ennopeptins.

Figure 15. Structure of tyrocidine A, and the average solution conformation determined by NMR.[91]

Figure 16. Structures of polymyxin B1 and E, and the average solution conformation from NMR studies.[187]

Figure 17. Structures of protegrin I and IB-367, and the average solution conformation of protegrin I in the membrane-bound dimer state (PDB 1ZY6).

Figure 18. Structure of BILB 2061 and ITMN-191.

Figure 19. Structure of Debio-25.

Figure 20. Structures of AMD3100 and AMD3465.

Figure 21. Structure of callipeltin A.

Figure 22. Structure of amphothericin B.

Figure 23. Structures of echinocandins.

Figure 24. Structure of aureobasidin A and conformation in the crystalline state

(CCDC 143108).

Figure 25. Structures of antimycin, UK2A and UK3A, and the conformation of antimycin A1 bound to mitochondrial cytochrome bc1 (PDB 1NTK).[188]

Figure 26. Structure of pseudomycins A-C.

Figure 27. Structure of emodepsipeptides.

Figure 28. Structure of PEM molecules. ß-Hairpin PEMs typically comprise a peptide loop (e.g. 12 residues (X1 - X12) are shown below), linked to a ß-hairpin-stabilizing template (e.g. the D-Pro-L-Pro dipeptide shown below). The residues may be proteinogenic or non-proteinogenic amino acids, or even peptoid or related building blocks. 36

Figure 29. Structures of protegrin I, tachyplesin I and polyphemusin II.

Figure 30. Antimicrobial PEMs based on the natural product protegrin I. Average solution NMR structures or mimetic 1 and 4 are also shown.

Figure 31. Structure of POL3026.

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