Natural Proline-Rich Cyclopolypeptides from Marine Organisms: Chemistry, Synthetic Methodologies and Biological Status

Abstract

Peptides have gained increased interest as therapeutics during recent years. More than 60 peptide drugs have reached the market for the benefit of patients and several hundreds of novel therapeutic peptides are in preclinical and clinical development. The key contributor to this success is the potent and specific, yet safe, mode of action of peptides. Among the wide range of biologically-active peptides, naturally-occurring marine-derived cyclopolypeptides exhibit a broad range of unusual and potent pharmacological activities. Because of their size and complexity, proline-rich cyclic peptides (PRCPs) occupy a crucial chemical space in drug discovery that may provide useful scaffolds for modulating more challenging biological targets, such as protein-protein interactions and allosteric binding sites. Diverse pharmacological activities of natural cyclic peptides from marine sponges, tunicates and cyanobacteria have encouraged efforts to develop cyclic peptides with well-known synthetic methods, including solid-phase and solution-phase techniques of peptide synthesis. The present review highlights the natural resources, unique structural features and the most relevant biological properties of proline-rich peptides of marine-origin, focusing on the potential therapeutic role that the PRCPs may play as a promising source of new peptide-based novel drugs.

Phakellistatins: An Underwater Unsolved Puzzle

“…Cβ and Cγ 13 C-NMR chemical shifts are indicative of the proline peptide bond conformations. A relatively large Δδ cβ-cγ difference (approximately 8–10 ppm) suggests a cis isomer, while a smaller difference (approximately 3–4 ppm) points towards a trans one [19]. In this case both 13 C-NMR and X-ray determination confirmed a trans , cis , cis geometry of the peptidyl-prolyl bonds for the proline named Pro 1 , Pro 3 , and Pro 6 , respectively.…”

“…Some of them act as specific modulators of pharmacological targets and are used in the clinic (e.g., tyrocidine, gramicidin S) and clinical trials (e.g., aplidine). The Pro residue plays an important structural role in the macrocycle for its innate ability to reduce the conformational flexibility and induce specific conformations, which is often translated in an improved bioactivity [19]. …”

“…Indeed, phakellistatin 10 showed an LC 50 of less than 10 −5 M against the MDA-MB-435 breast cancer cell line and total growth inhibition for two breast cancers and two CNS cancer cell lines at a concentration of less than 10 −6 M. Phakellistatin 11 presented a moderately lower level of in vitro activity as shown by an LC 50 less than 10 −5 M against the MDA-MB-435 breast cancer cell line and five other cell lines. It also achieved total growth inhibition for two breast cancers, one CNS cancer, one ovarian cancer, and one non-small cell lung cancer cell line at a concentration of less than 10 −7 M. Interestingly, the structural relationship to hymenamides, proline-rich cyclopeptides [19], suggested a common microorganism genesis or the defensive role in closely-related marine sponges.…”

First Total Synthesis and Biological Screening of a Proline-Rich Cyclopeptide from a Caribbean Marine Sponge

“…In comparison, marine sponge-derived heptacyclopeptide stylissamide G, with its characteristic pattern of ‘Pro’ and ‘Phe’ units in repeated manner i.e., two ‘Pro’ units separated by a ‘Phe’ unit, was of particular interest in the present study. Keeping in view the broad range of pharmacological activities possessed by natural cyclopolypeptides [24,25], including the biological potential of other stylissamides (e.g., inhibitory activity towards protein translation/synthesis by Stylissamide A [26], and inhibitory activity against migration of HeLa cells by Stylissamide X [27]), the present investigation was directed toward the synthesis and structure elucidation of stylissamide G by using a solution-phase technique to obtain a natural cyclooligopeptide in the quantitative yield in the laboratory. This study was in continuation of the efforts of our research group for the total synthesis of natural bioactive cyclic peptides of marine and plant origin [28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53].…”

Total Synthesis of a Natural Cyclooligopeptide From Fruits of Sugar-Apples

“…A natural cyclic pentapeptide, fanlizhicyclopeptide B was isolated from the fruits of Annona squamosa (sugar-apples) and its structure was elucidated by ESI MS/MS, 1D and 2D NMR data and chemical degradation (Wu et al 2014). Keeping in view broad range of pharmacological activities possessed by natural cyclopeptides (Fang et al 2016;Dahiya, 2013;Dahiya and Pathak, 2006a;Pathak and Dahiya, ISSN: 2249-6041 (Print); ISSN: 2249-9245 (Online) 2 2003) and in continuation of synthetic studies of our research group toward natural peptides and their analogs (Dahiya 2007a;2007b;2007c;2008a;2008b;2008c;2008d;Dahiya and Gautam, 2010a;2010b;2010c;2011a;2011b;2011c;2011d;Dahiya and Kaur, 2007a;2008a;Dahiya and Kumar, 2007;Dahiya and Pathak, 2006b;2007a;2007b;Dahiya and Sharma, 2008;Dahiya and Singh, 2017a;2017b;2017c;Dahiya et al 2006;2009a;2009b;2009c;Kumar et al 2017), the present investigation directed toward the synthesis, structure elucidation and the biological evaluation of a sugar-apple derived cyclopentapeptide, fanlizhicyclopeptide B for the antibacterial, antifungal and anthelmintic potential.…”