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Organic & Biomolecular Chemistry Organic & Biomolecular Chemistry Accepted Manuscript This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/obc Page 1 of 11 OrganicPlease & Biomoleculardo not adjust margins Chemistry Journal Name REVIEW Synthesis and Bioactivity of Antitubercular Peptides and Peptidomimetics: an Update Received 00th January 20xx, a a a,b Accepted 00th January 20xx Luis M. De Leon Rodriguez,* Harveen Kaur and Margaret A. Brimble* Manuscript DOI: 10.1039/x0xx00000x Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), an infection that has been declared a global public health emergency by the World Health Organization. Current anti-TB therapies are limited in their efficacy and have failed www.rsc.org/ to prevent the spread of TB, due to the long term drug compliance required and the genesis of multidrug-resistant strains (MDR). The number of chemotherapeutic agents currently available to treat MDR is limited, therefore there is a great need for new anti-TB drugs. Anti-TB peptides and peptidomimetics have emerged as an important and growing class of chemotherapeutic agents. This mini-review provides an update on peptides that exhibit very potent anti-TB activity, and their chemical syntheses, which could potentially be included in the pipeline for new anti-TB drug development. by existing Mtb drugs and new targets are listed in Table 1 and Accepted 1. Introduction Table 2 respectively. 5 The list is not exhaustive and only intends to illustrate the growing list of targets available to Mycobacterium tuberculosis (Mtb ) is a Gram-positive pathogen combat persistent Mtb and its mutants. responsible for most cases of tuberculosis (TB), which in 2013 alone resulted in 9 million new cases of TB and 1.5 million Table 1 Biomolecular targets inhibited by existing Mtb drugs deaths. 1 Typical medicines used to treat tuberculosis are small organic molecules such as isoniazid, rifampicin, pyrazinamide Anti-TB medicine Target and ethambutol, which are used as a first-line treatment Isoniazid Enoyl-acyl-carrier protein-reductase option. However, if resistance to the first-line anti-TB drugs is Rifampicin DNA dependent RNA polymerase observed, then second-line drugs are administered, which Pyrazinamide Fatty acid synthase include aminoglycosides, D-cycloserine, ethionamide, Ethambutol Arabinosyltransferase protionamide, capreomycin (a cyclic pentapeptide), Ethionamide β-ketoacyl ACP synthase Chemistry aminosalicylic acid and fluoroquinolones. 2 Usually, these drugs D-cycloserine D-alanyl-D-alanine ligase are effective if the patient complies with the long treatment Aminoglycosides Ribosome period, but lack of compliance can lead to the development of Capreomycin Fluoroquinolone DNA gyrase multidrug resistant (MDR) or extremely drug resistant (XDR) Bedaquiline 6 ATP synthase (new target) Mtb strains, which are more difficult to treat. Bedaquiline is an anti-TB drug recently approved by the FDA for the treatment of MDR cases where other drugs have failed. However, Table 2 New biomolecular targets for anti-TB drug development. 5 bacterial resistance and poor patient outcome, has limited the New Targets application of bedaquiline as a second-line medication.3,4 Therefore, due to the growing resistance to currently available Deformylase Mycothiol ligase anti-TB therapeutics, there is a pressing need for the Maltosyltransferase Mycolic acid cyclopropanation, development of new antitubercular agents. In particular, the L,D -transpeptidase Methionine aminopeptidase Decaprenylphosphoryl-β-D- The proteasome complex discovery of molecules that aim for new biomolecular Mtb Biomolecular targets is important for the future development of drugs to ribose 2’-epimerase Isocitrate lyase ATP phosphoribosyl transferase Cell wall lipid II or III treat MDR and XDR strains. The biomolecular targets inhibited & Naturally occurring peptides and their derivatives are an important and growing class of biopharmaceuticals with a current success rate approximately twice that of small molecule drugs. 7 This has been attributed to the advantages of peptides over their small organic counterparts, such as increased target affinity, and fewer off-target side-reactions and thus less side effects. Organic This journal is © The Royal Society of Chemistry 20xx J. Name ., 2015, 00 , 1-3 | 1 Please do not adjust margins OrganicPlease & Biomoleculardo not adjust margins Chemistry Page 2 of 11 ARTICLE Journal Name H-Ala- 2Cys-Tyr- 4Cys-Arg-Ile-Pro-Ala- 9Cys-Ile-Ala-Gly-Glu-Arg-Arg-Tyr-Gly-Thr- 19 Cys-Ile-Tyr-Gln-Gly-Arg-Leu-Trp-Ala-Phe- 29 Cys- 30 Cys-OH HNP-1, 1 NH 2 H-Trp-Lys-Trp-Leu-Lys-Lys-Trp-Ile-Lys-Gly-NH 2 R O O NH 2 WKWLKKWIK, 2 H H2N N NH 2 N N O O O H H H O N N N NH HN O C13 H27 N N NH 2 H H OH O N N NH 2 H O O O H N N H H N O O HN O O capreomycin IA R = OH , 5 BB-3497, 3 NH HN N 2 1-C13 4mer , 4 H IB R = H , 6 OH O Manuscript O O O O O C8H17 H H H H N N N N N OH N N N N N H H H H O O O O R trichoderin A, R = CH 3, 7 B, R = H , 8 4 3Gln Leu 4Arg 5 3Arg 5Leu 2Ser Val 2Leu 1Gly 6Tyr 6Phe 1Gly Accepted 7Arg 7Ala O (8Glu) (8Asp) NH O NH O 9Trp- 10 Val- 11 Gly- 12 His- 13 Ser- 14 Asn- 15 Val- 16 Ile- 17 Lys- 18 Pro-OH O 9 10 11 12 13 14 15 16 Gln- Leu- Val- Gly- Arg- Arg- Asn- Ile-OCH 3 lariatin A, 9 lassomycin, 10 NH O HN O HO O O H H N N N H N N O NH HN H O O O O H2N O NH HN O N O H Chemistry O O N O R O N N NH O N N H2N O wollamide A, R = CH 3, 12 H H H N N O B, R = H , 13 O N O H O ecumicin, 11 OH O NH 2 O O O OH H H H HN N N N H N N N N N H H H O H N O O O NH O O O OH O N H O HN N O HN O O H N O 2 O N NH O HN O H NH O O O O NH O HN NH N N Biomolecular H O HO & HN NH callyaerin A, 14 teixobactin, 15 HN Fig 1 . Structures of potent antitubercular peptides and peptidomimetics. Organic 2 | J. Name ., 2015, 00 , 1-3 This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Page 3 of 11 OrganicPlease & Biomoleculardo not adjust margins Chemistry Journal Name ARTICLE Table 3. Potent antitubercular peptides and peptidomimetics discussed in this review. Peptide Source MIC, µ g/mL (strain ) Cytoxicity Mechanism/Target Ref. HNP-1 ( 1) Innate immunity 2.5 (H37Rv) None Microbial membrane disruption 12 13 WKWLKKWIK ( 2) (2013) Peptide library 1.5 MIC 90 (H37Rv) Low against macrophage- Possibly microbial membrane like human THP-1 cells disruption 15 BB-3497 ( 3) (2001) Metalloenzyme 0.25 MIC 90 (H37Rv) Not determined Peptide deformylase inhibitor library 14 16 1-C13 4mer (4) (2011) Synthetic 5.3 (BCG) None against Raw 264.7 Microbial membrane disruption 5.5 (H37Rv) and J774 mouse macro- phage cell lines 17 capreomycin ( 5,6 ) (1960) Streptomyces 2.0 (H37Rv) Ototoxic Ribosome Capreolus 18,19 trichoderin A ( 7) (2010) Marine sponge- 0.02 (BCG) Not determined ATP synthase Manuscript derived fungus of 0.12 (H37Rv) trichoderin B ( 8) Trichoderma sp. 0.02 (BCG) Not determined ATP synthase 18,19 0.13 (H37Rv) lariatin A ( 9) (2006) Rhodococcus 0.39 (H37Rv) Not determined Inhibits cell wall biosynthesis 20 jostii K01-B0171 lassomycin ( 10 ) (2014) Collection of soil 0.78-1.56 (H37Rv) None against NIH 3T3 and ATP-Dependent Protease 21 actinomycetes HepG2 cells ClpC1P1P2 ecumicin ( 11 ) (2014) Nonomuraea 0.26 (H37Rv) None against VERO cells ClpC1 ATPase complex 22 sp . MJM5123 wollamide A (12 ) (2014) Streptomyces 2.11 (BCG) None against macrophages Not determined 23 nov. sp. (MST- Accepted wollamide B (13 ) 115088) 2.29 (BCG) None against macrophages Not determined 23 24 callyaerin A ( 14 ) (2015) Marine sponge 2.0 MIC 90 None against THP-1 and Not determined (Callyspongia aerizusa ) MRC-5 cell lines teixobactin ( 15 ) (2015) β-proteobacterium 0.16 (H37Rv) None against NIH/3T3 mouse Lipid II and III 25 Eleftheria terrae embryonic fibroblast MIC 90 = minimal inhibitory concentration for 90% bacterial growth inhibition. However, peptides containing only natural ribosomally synthesised amino acids have some disadvantages, such as poor in vivo stability and oral bioavailability, which limits their 2. Innate Immunity and Synthetic Peptides Chemistry potential use as therapeutics. Peptide in vivo instability can be The human neutrophil tetradecapeptide 1 (HNP-1, 1) is one of overcome by introducing unnatural amino acids the six human α-defensins which are part of the arsenal of (posttranslationally modified amino acids, D-amino acids, N- innate immunity to combat infectious microorganisms.
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