764 CHIMIA 2009, 63, No. 11 SWISS CHEMISTS IN THE USA doi:10.2533/chimia.2009.764 Chimia 63 (2009) 764–775 © Schweizerische Chemische Gesellschaft Peptide-Like Molecules (PLMs): A Journey from Peptide Bond Isosteres to Gramicidin S Mimetics and Mitochondrial Targeting Agents Peter Wipf*, Jingbo Xiao, and Corey R. J. Stephenson Abstract: Peptides are natural ligands and substrates for receptors and enzymes and exhibit broad physiological effects. However, their use as therapeutic agents often suffers from poor bioavailability and insufficient membrane permeability. The success of peptide mimicry hinges on the ability of bioisosteres, in particular peptide bond replacements, to adopt suitable secondary structures relevant to peptide strands and position functional groups in equivalent space. This perspective highlights past and ongoing studies in our group that involve new methods development as well as specific synthetic library preparations and applications in chemical biology, with the goal to enhance the use of alkene and cyclopropane peptide bond isosteres. Keywords: Alkene peptide bond isosteres · Cyclopropanes · Gramicidin S · Mitochondrial targeting · Organic synthesis Peter Wipf was born 1. Introduction effective disruptors of protein–protein in Aarau, Switzer- interactions, and, in many instances, al- land. He received his Biopolymers represent a special class lowing for useful therapeutic activities. A Dipl. Chem. in 1984 of natural products, offering unique op- Sunesis-Merck collaboration discovered and his PhD in 1987 portunities for small molecule mimicry. aminoethylene isosteres 1 as potent in- from the University Biopolymer-derived compounds can ex- hibitors of the β-site amyloid precursor of Zurich under the ploit drug–target contacts that closely protein cleaving enzyme (Fig. 1).[1] The direction of Profes- parallel those found in native systems, selective cathepsin K inhibitor 2,devel- sor Heinz Heimgart- such as protein–protein and protein– oped by a Celera-Merck team, featured ner. After a Swiss lipid interactions. This gross structural a trifluoroethylamine isostere developed NSF postdoctoral fellowship with Profes- homology can often be advantageous in by Zanda’s group.[2,3] The Fujii group at sor Robert E. Ireland at the University of developing new drug leads; i.e. synthetic Kyoto University has a long tradition in Virginia,Wipf began his appointment at the materials can be more readily recognized developing methodology for (E)-alkene University of Pittsburgh in the fall of 1990. and integrated into native biochemical peptide isostere synthesis, and recently His research interests include the total syn- processes. Moreover, physiological bio- reported cyclic RGD mimetics 3 based on thesis of natural products, organometallic polymer degradation typically leads to this concept.[4] Another creative design and heterocyclic chemistry, combinatorial, metabolites that are tolerated in vivo and for amide bond replacements is being medicinal and computational chemistry. readily excreted. However, hydrolytic pursued by the Sieburth group at Temple His group studies chemical reactivity and degradation is also among the native University, which yielded 4, a silanediol- the use of synthesis to augment the chemi- biochemical processes that often func- based inhibitor of angiotensin-converting cal toolbox and develop new therapeutic tion to limit drug lifetime. These con- enzyme.[5] strategies. The discovery of fundamentally siderations, as well as the inherent dif- With the goal of developing a unified new reaction pathways is stimulated by ex- ficulties of biopolymers to pass through approach toward constructing biopoly- ploratory studies of transition metal com- membranes, have been among the prime mer surrogates, we have exploited new plexes, in particular zirconocenes. contributory factors driving the develop- reaction technologies developed in our ment of synthetic biopolymer surrogates. laboratory for generating structurally di- Ideally, the latter can mimic the tertiary verse biopolymer-like compounds, spe- structure and function of native materials cifically peptide-like molecules (PLMs). while, simultaneously, displaying immu- Our building blocks include cyclopro- nity to hydrolytic degradation and taking pane-substituted δ- and γ-amino acids, advantage of active or passive membrane β,γ-unsaturated δ-amino acids, β-sub- transfer processes. stituted β-amino acids, and α,β-disub- *Correspondence: Prof. Dr. P. Wipf Significantly, synthetic biopolymer- stituted β-amino acids; with structural University of Pittsburgh inspired materials either composed of diversity originating both from building Department of Chemistry Center for Chemical Methodologies & Library or incorporating unnatural α-, β-, and γ- block diversity as well as sequence di- Development amino acids, peptoids, peptide isosteres, versity. In addressing the latter, each of Pittsburgh, PA 15260 and other amino acid surrogates have al- these building block families are readily Tel.: +1 412 624 8606 ready been found to exhibit folding be- incorporated into standard peptide syn- Fax: +1 412 624 0787 E-mail: [email protected] haviors similar to native peptides, to be thesis protocols, thereby, accelerating SWISS CHEMISTS IN THE USA CHIMIA 2009, 63, No. 11 765 Fig. 1. Recent and enzymes. Recently, considerable ad- examples of vances have been made in the targeted de- CF H NH2 H 3 H biologically active N CN livery of peptides, and their appeal as phar- N N N N H peptide bond [20] O O O O maceuticals is surging. Modifications of F isosteres. 12native peptide sequences and introduction S O O of bioisosteres represent complementary strategies to harness desirable biological CO2H Ph H effects. The success of peptide mimicry N O hinges on the ability of bioisosteres, in par- NH OH O HO O H ticular peptide bond replacements, to adopt H Ph N Si N HN NH N suitable secondary structures relevant to O O CO H O Ph 2 peptide strands and position functional H2N N H 34groups into equivalent space. The replacement of the scissile pep- tide bond 5 with nonhydrolyzable iso- Fig. 2. Amide bond steric functions is an important design R O motif in medicinal chemistry.[21] In recent i+1 Ri+1 O linkage in peptides (5) and common isosteric years, many nonhydrolyzable mimetics N N replacements 6–11. have been developed, including (E)-al- H R R H i+2 O Ri+2 67 kene (ψ[(E)-C(R)=CH]) 6,[22] ketometh- ylene (ψ[COCH ]) 7,[23] hydroxyethylene R O 2 Ri+1 O i+1 H Ri+1 OH O (ψ[CH(OH)CH ]) 8,[24] dihydroxyethyl- 2 N [25] N N N ene (ψ[CH(OH)CHOH]) 9, hydroxy- H H O R H ethylamine (ψ[CH(OH)CH NH]) 10,[26] OH Ri+2 i+2 OH Ri+2 2 895 and methyleneamine (ψ[CH NH]) 11[2,3,27] 2 R O moieties (Fig. 2). Prior studies in our H OH H O i+1 H N laboratories have mainly focused on the N N N H synthesis, conformational analysis, and R Ri+1 10 Ri+2 11 i+2 biological applications of alkene peptide isosteres in δ-amino acid building blocks 6 and the corresponding cyclopropane ana- logs 12 and 13 (Fig. 3).[28] The relatively rigid, trisubstituted (E)-alkenes 6 (ψ[(E)- access to the targeted biological pathway macroscopic physical or biological prop- C(R)=CH]) represent useful, conforma- disruptors and functional mimetics. erties. The promising range of applica- tionally preorganized structural mimetics In recent years, β- and γ-amino acids[6] tions for foldamers that are not exclusive- and have been used as surrogates of hydro- have been studied extensively, and, due ly composed of the standard α-amino acid lytically labile amide bonds in a number of to a greater understanding of their fold- residues justifies a further expansion to enzyme inhibitors.[29] ing properties coupled with the power of include γ- and δ-amino acids and compos- The primary objective of the alkene chemical genetics,[7] the structure-based ites of mixed constitution. In all cases, it peptide bond isostere strategy is the accu- design[8] of new therapeutic agents has is critical to develop new synthetic meth- rate mimicry of the geometry of the peptide been enabled. Much like their natural odologies that allow rapid and scaleable bond, particularly its rigidity, bond angle, α-amino counterparts, β- and γ-amino access to these materials as well as per- and length. We have constructed several acids have been found to form a variety form fundamental studies elucidating the analogs of the cyclodecapeptide gramici- of helical and pleated sheet-like structural factors that influence secondary structure. din S (GS) in order to study the effects of motifs. Oligomers that adopt predictable PLMs with γ- and δ-amino acid resi- specific amide bond replacements on the conformations in aqueous solution are dues have been studied much less than the overall conformation and the biological ac- accessible via modular chemistry and en- corresponding β-peptides, but there is lit- tivity of this antibiotic.[30] We were able to able the display of a wide range of func- tle doubt that these derivatives offer simi- demonstrate that key replacements of the tional groups, which renders them attrac- larly enticing opportunities for supramo- natural peptide sequence at the D-Phe-Pro [17] tive for creating new types of biologically lecular chemistry and drug discovery. β-turn as well as the Leu-D-Phe β-sheet po- active agents.[9] This concept has been We have developed versatile and innova- sitions conserved the parent GS secondary validated and broadly popularized with tive approaches toward these compound structure as well as its biological effects. β-peptides.[10]