Abstract
The pharmaceutical industry has focused mainly in the development of small-molecule entities intended for oral administration for the past decades. As a result, the majority of existing drugs address only a narrow range of biological targets. In the era of post-genomics, transcriptomics, and proteomics, there is an increasing interest on larger modulators of proteins that can span larger surfaces, access new therapeutic mechanisms of action, and provide greater target specificity. Traditional drug-like molecules developed using “rule-of-five” (Ro5) guidelines have been proven ineffective against a variety of challenging targets, such as protein–protein interactions, nucleic acid complexes, and antibacterial modalities. However, natural products are known to be effective at modulating such targets, leading to a renewed focus by medicinal chemists on investigating underrepresented chemical scaffolds associated with natural products. Here we describe recent efforts toward identification of novel natural cyclopeptides and macrocycles as well as selected medicinal chemistry strategies to increase drug-like properties or further exploration of their activity.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Hill TA, Shepherd NE, Diness F, Fairlie DP (2014) Constraining cyclic peptides to mimic protein structure motifs. Angew Chem Int Ed Engl 53:13020–13041
Wessjohann LA, Ruijter E, Garcia-Rivera D, Brandt W (2005) What can a chemist learn from nature’s macrocycles? A brief, conceptual view. Mol Divers 9:171–186
Naylor MR, Bockus AT, Blanco MJ, Lokey RS (2017) Cyclic peptide natural products chart the frontier of oral bioavailability in the pursuit of undruggable targets. Curr Opin Chem Biol 38:141–147
Wetzler M, Hamilton P (2018) Peptides as therapeutics. In: Koutsopoulos S (ed) Peptide applications in biomedicine, biotechnology and bioengineering. Woodhead Publishing Elsevier Ltd.
Qvit N, Rubin SJ, Urban TJ, Mochly-Rosen D, Gross ER (2017) Peptidomimetic therapeutics: scientific approaches and opportunities. Drug Discov Today 22:454–462
Pomilio AB, Battista ME, Vitale AA (2006) Naturally-occurring cyclopeptides: structures and bioactivity. Curr Org Chem 10:2075–2121
Bockus AT, McEwen CM, Lokey RS (2013) Form and function in cyclic peptide natural products: a pharmacokinetic perspective. Curr Top Med Chem 13:821–836
Ghadiri MR, Granja JR, Milligan RA, McRee DE, Khazanovich N (1993) Self-assembling organic nanotubes based on a cyclic peptide architecture. Nature 366:324–327
Rosenthal-Aizman K, Svensson G, Undén A (2004) Self-assembling peptide nanotubes from enantiomeric pairs of cyclic peptides with alternating D and L amino acid residues. J Am Chem Soc 126:3372–3373
Qian Z, Dougherty PG, Pei D (2017) Targeting intracellular protein–protein interactions with cell-permeable cyclic peptides. Curr Opin Chem Biol 38:80–86
Senthilkumar B, Rajasekaran R (2017) Analysis of the structural stability among cyclotide members through cystine knot fold that underpins its potential use as a drug scaffold. Inter J Peptide Res Therap 23(1):1
Molesini B, Treggiari D, Dalbeni A, Minuz P, Pandolfini T (2017) Plant cystine-knot peptides: pharmacological perspectives. Br J Clin Pharmacol 83:63–70
Dobson CM (2004) Chemical space and biology. Nature 432:824–828
Borel J.F. (1982) History of cyclosporin A and its significance in immunology. In: Cyclosporin A, pp 5–17
Borel JA, Feurer C, Gubler HU, Stähelin H (1976) Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions 6:468–475
Wenger RM (1984) Synthesis of cyclosporine. Total syntheses of ‘cyclosporin A’ and ‘cyclosporin H’, two fungal metabolites isolated from the species Tolypocladium inflatum GAMS. Helv Chim Acta 67:502–525
Sweeney ZK, Fu J, Wiedmann B (2014) From chemical tools to clinical medicines: nonimmunosuppressive cyclophilin inhibitors derived from the cyclosporin and sanglifehrin scaffolds. J Med Chem 57:7145–7159
Bai Y, King C, Francis C, Gooch J (2017) Cyclosporin A alters expression of renal MicroRNAs: new insights into calcineurin inhibitor nephrotoxicity. FASEB J 31:757–713
Naicker S, Yatscoff RW, Foster RT (2009) Deuterated cyclosporine analogs and methods of making the same. US Patent 7(521):421
Ahlbach CL, Lexa KW, Bockus AT, Chen V, Crews P, Jacobson MP, Lokey RS (2015) Beyond cyclosporine A: conformation-dependent passive membrane permeabilities of cyclic peptide natural products. Future Med Chem 7:2121–2130
Wang CK, Swedberg JE, Harvey PJ, Kaas Q, Craik DJ (2018) Conformational flexibility is a determinant of permeability for cyclosporin. J Phys Chem B 122:2261–2276
Rossi Sebastiano M, Doak BC, Backlund M, Poongavanam V, Over B, Ermondi G, Caron G, Matsson P, Kihlberg J (2018) Impact of dynamically exposed polarity on permeability and solubility of chameleonic drugs beyond the rule of 5. J Med Chem 61:4189–4202
Räder AF, Reichart F, Weinmüller M, Kessler H (2018) Improving oral bioavailability of cyclic peptides by N-methylation. Bioorg Med Chem 26:2766–2773
Consden R, Gordon AH, Martin AJ, Synge RL (1947) Gramicidin S: the sequence of the amino-acid residues. Biochem J 41:596
Kondejewski LH, Farmer SW, Wishart DS, Hancock RE, Hodges RS (1996) Gramicidin S is active against both gram-positive and gram-negative bacteria. Chem Biol Drug Des 47:460–466
Abraham T, Prenner EJ, Lewis RN, Mant CT, Keller S, Hodges RS, McElhaney RN (2014) Structure–activity relationships of the antimicrobial peptide gramicidin S and its analogs: aqueous solubility, self-association, conformation, antimicrobial activity and interaction with model lipid membranes. Biochim Biophys Acta 1838:1420–1429
Meanwell NA (2011) Synopsis of some recent tactical application of bioisosteres in drug design. J Med Chem 54:2529–2591
Xiao J, Weisblum B, Wipf P (2005) Electrostatic versus steric effects in peptidomimicry: synthesis and secondary structure analysis of gramicidin S analogues with (E)-alkene peptide isosteres. J Am Chem Soc 127:5742–5743
Davies J, Davies D (2010) Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev 74:417–433
Carney DW, Schmitz KR, Truong JV, Sauer RT, Sello JK (2014) Restriction of the conformational dynamics of the cyclic acyldepsipeptide antibiotics improves their antibacterial activity. J Am Chem Soc 136:1922–1929
Goodreid JD, Wong K, Leung E, McCaw SE, Gray-Owen SD, Lough A, Houry WA, Batey RA (2014) Total synthesis and antibacterial testing of the A54556 cyclic acyldepsipeptides isolated from Streptomyces hawaiiensis. J Nat Prod 77:2170–2181
Socha AM, Tan NY, LaPlante KL, Sello JK (2010) Diversity-oriented synthesis of cyclic acyldepsipeptides leads to the discovery of a potent antibacterial agent. Bioorganic Med Chem 18:7193–7202
Goodreid JD, Janetzko J, Santa Maria Jr JP, Wong KS, Leung E, Eger BT, Bryson S, Pai EF, Gray-Owen SD, Walker S, Houry WA. (2016) Development and characterization of potent cyclic acyldepsipeptide analogues with increased antimicrobial activity. J Med Chem 59:624–646
Naylor M, Ly A, Schwochert J, Desai P, Gonzalez Valcarcel IC, Barrett J, Sawada G, Blanco MJ, Lokey S (2016) Amide-to-ester substitutions modify the permeability and ADME properties of natural and synthetic cyclic peptides. From abstracts of papers, 252nd ACS National Meeting & Exposition, Philadelphia, PA, United States, August 21–25, MEDI-344
Lukat P, Katsuyama Y, Wenzel S, Binz T, König C, Blankenfeldt W, Brönstrup M, Müller R (2017) Biosynthesis of methyl-proline containing griselimycins, natural products with anti-tuberculosis activity. Chem Sci 8:7521–7527
Kling A, Lukat P, Almeida DV, Bauer A, Fontaine E, Sordello S, Zaburannyi N, Herrmann J, Wenzel SC, König C, Ammerman NC (2015) Targeting DnaN for tuberculosis therapy using novel griselimycins. Science 348:1106–1112
Dong M, Pfeiffer B, Altmann KH (2017) Recent developments in natural product-based drug discovery for tuberculosis. Drug Discov Today 22:585–591
Salvador-Reyes LA, Luesch H (2015) Biological targets and mechanisms of action of natural products from marine cyanobacteria. Nat Prod Rep 32:478–503
Taori K, Paul VJ, Luesch H (2008) Structure and activity of largazole, a potent antiproliferative agent from the Floridian marine cyanobacterium Symploca sp. J Am Chem Soc 130:1806–1807
Poli G, Di Fabio R, Ferrante L, Summa V, Botta M (2017) Largazole analogues as histone deacetylase inhibitors and anticancer agents: an overview of structure–activity relationships. ChemMedChem 12:1917–1926
Chen QY, Chaturvedi PR, Luesch H (2018) Process development and scale-up total synthesis of Largazole, a potent Class I histone deacetylase inhibitor. Org Process Res Dev 22:190–199
Cole KE, Dowling DP, Boone MA, Phillips AJ, Christianson DW (2011) Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases. J Am Chem Soc 133:12474–12477
Almaliti J, Al-Hamashi AA, Negmeldin AT, Hanigan CL, Perera L, Pflum MK, Casero Jr RA, Tillekeratne LV. (2016) Largazole analogues embodying radical changes in the depsipeptide ring: development of a more selective and highly potent analogue. J Med Chem 59:10642–10660
Steenbergen JN, Alder J, Thorne GM, Tally FP (2005) Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections. J Antimicrob Chemother 55:283–288
Bionda N, Pitteloud JP, Cudic P (2013) Cyclic lipodepsipeptides: a new class of antibacterial agents in the battle against resistant bacteria. Future Med Chem 5:1311–1330
Daley P, Louie T, Lutz JE, Khanna S, Stoutenburgh U, Jin M, Adedoyin A, Chesnel L, Guris D, Larson KB, Murata Y (2017) Surotomycin versus vancomycin in adults with Clostridium difficile infection: primary clinical outcomes from the second pivotal, randomized, double-blind, Phase 3 trial. J Antimicrob Chemother 72:3462–3470
Yin N, Li J, He Y, Herradura P, Pearson A, Mesleh MF, Mascio CT, Howland K, Steenbergen J, Thorne GM, Citron D (2015) Structure–activity relationship studies of a series of semisynthetic lipopeptides leading to the discovery of Surotomycin, a novel cyclic lipopeptide being developed for the treatment of Clostridium difficile-associated diarrhea. J Med Chem 58:5137–5142
Lee CH, Patino H, Stevens C, Rege S, Chesnel L, Louie T, Mullane KM (2016) Surotomycin versus vancomycin for Clostridium difficile infection: Phase 2, randomized, controlled, double-blind, non-inferiority, multicentre trial. J Antimicrob Chemother 71:2964–2971
Borders DB, Leese RA, Jarolmen H, Francis ND, Fantini AA, Falla T, Fiddes JC, Aumelas A (2007) Laspartomycin, an acidic lipopeptide antibiotic with a unique peptide core. J Nat Prod 70:443–446
Kleijn LH, Oppedijk SF, ‘t Hart P, Van Harten RM, Martin-Visscher LA, Kemmink J, Breukink E, Martin NI. (2016) Total synthesis of laspartomycin C and characterization of its antibacterial mechanism of action. J Med Chem 59:3569–3574
Mi Y, Zhang J, He S, Yan X (2017) New peptides isolated from marine cyanobacteria, an overview over the past decade. Mar Drugs 15:132
Reese MT, Gulavita NK, Nakao Y, Hamann MT, Yoshida WY, Coval SJ, Scheuer PJ (1996) Kulolide: a cytotoxic depsipeptide from a cephalaspidean mollusk, Philinopsis speciosa. J Am Chem Soc 118:11081–11084
Boudreau PD, Byrum T, Liu WT, Dorrestein PC, Gerwick WH (2012) Viequeamide A, a cytotoxic member of the kulolide superfamily of cyclic depsipeptides from a marine button cyanobacterium. J Nat Prod 75:1560–1570
Wang D, Song S, Tian Y, Xu Y, Miao Z, Zhang A (2013) Total synthesis of the marine cyclic depsipeptide viequeamide A. J Nat Prod 76:974–978
Almaliti J, Malloy KL, Glukhov E, Spadafora C, Gutiérrez M, Gerwick WH (2017) Dudawalamides A–D, Antiparasitic Cyclic Depsipeptides from the Marine Cyanobacterium Moorea producens. J Nat Prod 80:1827–1836
Just-Baringo X, Albericio F, Álvarez M (2014) Chiral thiazoline and thiazole building blocks for the synthesis of peptide-derived natural products. Curr Top Med Chem 14:1244–1256
Nielsen DS, Hoang HN, Lohman RJ, Diness F, Fairlie DP (2012) Total synthesis, structure, and oral absorption of a thiazole cyclic peptide, sanguinamide A. Org Lett 14:5720–5723
Bockus AT, Schwochert JA, Pye CR, Townsend CE, Sok V, Bednarek MA, Lokey RS (2015) Going out on a limb: delineating the effects of β-branching, N-methylation, and side chain size on the passive permeability, solubility, and flexibility of Sanguinamide A analogues. J Med Chem 58:7409–7418
Desai PV, Raub TJ, Blanco MJ (2012) How hydrogen bonds impact P-glycoprotein transport and permeability. Bioorg Med Chem Lett 22:6540–6548
Zipperer A, Konnerth MC, Laux C, Berscheid A, Janek D, Weidenmaier C, Burian M, Schilling NA, Slavetinsky C, Marschal M, Willmann M (2016) Human commensals producing a novel antibiotic impair pathogen colonization. Nature 535:511–516
Krismer B, Peschel A, Grond S, Zipperer A, Konnerth MC, Janek D (2016) Patent PCT Int Appl WO 2016151005
Mousa WK, Athar B, Merwin NJ, Magarvey NA (2017) Antibiotics and specialized metabolites from the human microbiota. Nat Prod Rep 4:1302–1331
Sekizawa R, Momose I, Kinoshita N, Naganawa H, Hamada M, Muraoka Y, Iinuma H, Takeuchi T (2001) Isolation and structural determination of phepropeptins A, B, C, and D, new proteasome inhibitors, produced by Streptomyces sp. J Antibiot 54:874–881
Schwochert J, Lao Y, Pye CR, Naylor MR, Desai PV, Gonzalez Valcarcel IC, Barrett JA, Sawada G, Blanco MJ, Lokey RS (2016) Stereochemistry balances cell permeability and solubility in the naturally derived phepropeptin cyclic peptides. ACS Med Chem Lett 7:757–761
Safavi-Hemami H, Brogan SE, Olivera BM (2018) Pain therapeutics from cone snail venoms: from Ziconotide to novel non-opioid pathways. J Proteomics 190:12–20
Newcomb R, Abbruscato TJ, Singh T, Nadasdi L, Davis TP, Miljanich G (2000) Bioavailability of Ziconotide in brain: influx from blood, stability, and diffusion. Peptides 21:491–501
Schmidtko A, Lötsch J, Freynhagen R, Geisslinger G (2010) Ziconotide for treatment of severe chronic pain. Lancet 375:1569–1577
Thell K, Hellinger R, Sahin E, Michenthaler P, Gold-Binder M, Haider T, Kuttke M, Liutkevičiūtė Z, Göransson U, Gründemann C, Schabbauer G (2016) Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis. Proc Natl Acad Sci U S A 113:3960–3965
Aulakh VS, Ciufolini MA (2011) Total synthesis and complete structural assignment of thiocillin I. J Am Chem Soc 133:5900–5904
Just-Baringo X, Albericio F, Álvarez M (2014) Thiopeptide antibiotics: retrospective and recent advances. Mar Drugs 12:317–351
Tran HL, Lexa KW, Julien O, Young TS, Walsh CT, Jacobson MP, Wells JA (2017) Structure–activity relationship and molecular mechanics reveal the importance of ring entropy in the biosynthesis and activity of a natural product. J Am Chem Soc 139:2541–2544
Oku N, Takada K, Fuller RW, Wilson JA, Peach ML, Pannell LK, McMahon JB, Gustafson KR (2010) Isolation, structural elucidation, and absolute stereochemistry of enigmazole A, a cytotoxic phosphomacrolide from the Papua New Guinea marine sponge Cinachyrella enigmatica. J Am Chem Soc 132:10278–10285
Ai Y, Kozytska MV, Zou Y, Khartulyari AS, Maio WA, Smith AB III (2018) Total synthesis of the marine phosphomacrolide, (−)-Enigmazole A, exploiting multicomponent Type I Anion Relay Chemistry (ARC) in conjunction with a late-stage Petasis–Ferrier union/rearrangement. J Org Chem 83:6110–6126
Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ (2001) In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res 61:1013–1021
Aicher TD, Buszek KR, Fang FG, Forsyth CJ, Jung SH, Kishi Y, Matelich MC, Scola PM, Spero DM, Yoon SK (1992) Total synthesis of halichondrin B and norhalichondrin B. J Am Chem Soc 114:3162–3164
Zheng W, Seletsky BM, Palme MH, Lydon PJ, Singer LA, Chase CE, Lemelin CA, Shen Y, Davis H, Tremblay L, Towle MJ (2004) Macrocyclic ketone analogues of halichondrin B. Bioorg Med Chem Lett 14:5551–5554
Cortes J, Vahdat L, Blum JL, Twelves C, Campone M, Roché H, Bachelot T, Awada A, Paridaens R, Goncalves A, Shuster DE (2010) Phase II study of the halichondrin B analog eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine. J Clin Oncol 28:3922–3928
Camarero JA (2017) Cyclotides, a versatile ultrastable micro-protein scaffold for biotechnological applications. Bioorg Med Chem Lett 27:5089–5099
Eliasen R, Daly NL, Wulff BS, Andresen TL, Conde-Frieboes KW, Craik DJ (2012) Design, synthesis, structural and functional characterization of novel melanocortin agonists based on the cyclotide kalata B1. J Biol Chem 287:40493–40501
Tran D, Tran PA, Tang YQ, Yuan J, Cole T, Selsted ME (2002) Homodimeric theta-defensins from rhesus macaque leukocytes: isolation, synthesis, antimicrobial activities, and bacterial binding properties of the cyclic peptides. J Biol Chem 277:3079–3084
Reichlin S (1983) Somatostatin. N Engl J Med 309:1495–1501
Donaldson ZR, Young LJ (2008) Oxytocin, vasopressin, and the neurogenetics of sociality. Science 322:900–904
Beard R, Stucki A, Schmitt M, Py G, Grundschober C, Gee AD, Tate EW (2018) Building bridges for highly selective, potent and stable oxytocin and vasopressin analogs. Bioorg Med Chem 26:3039–3045
Poongavanam V, Doak BC, Kihlberg J (2018) Opportunities and guidelines for discovery of orally absorbed drugs in beyond rule of 5 space. Curr Opin Chem Biol 44:23–29
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Blanco, MJ. (2019). Building upon Nature’s Framework: Overview of Key Strategies Toward Increasing Drug-Like Properties of Natural Product Cyclopeptides and Macrocycles. In: Goetz, G. (eds) Cyclic Peptide Design. Methods in Molecular Biology, vol 2001. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9504-2_10
Download citation
DOI: https://doi.org/10.1007/978-1-4939-9504-2_10
Published:
Publisher Name: Humana, New York, NY
Print ISBN: 978-1-4939-9503-5
Online ISBN: 978-1-4939-9504-2
eBook Packages: Springer Protocols