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Coibamide A, a cyclic depsipeptide isolated from a Panamanian marine cyanobacterium, shows potent cytotoxic activity via the inhibition of the Sec61 translocon. We designed a coibamide A mimetic in which the ester linkage between MeThr and d-MeAla in coibamide A was replaced with an alkyl linker to provide a stable macrocyclic scaffold possessing a...
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... obtain further SAR information on the backbone conformations of 2a, we then designed and synthesized a series of derivatives substituted with an N-demethyl or Damino acid ( Table 2). Removal of the N α -methyl group from MeAla, 3 MeLeu 4 , and MeLys(Me) 5 in the N-terminal chain resulted in decreased cytotoxicities [IC 50 (8a) = 2.2 μM; IC 50 (8b) = 3.4 μM; IC 50 (8c) = 6.4 μM], suggesting that Nmethylation induces structural organization in the N-terminal chain, which is important for biological action. ...Context 2
... also assessed the cytotoxicities of epimers of peptide 2a in which one of the component amino acids in the macrocycle was replaced with a D-amino acid (Table 2) . The other epimers 9a−c and 9e showed no cytotoxicity, demonstrating that the all-L-configuration in the macrocycle of 2a is necessary for potent bioactivity. ...Citations
... The presence of Nmethylated amino acids in coibamide A influence peptide stability against degradation. While simplification of the methylated residues MeSer(Me) with MeAla can be tolerated for bioactivity, N-methylation was maintained in both cases (Kitamura et al. 2022). In the case of octapeptides 1-6, Nmethylation was not included as a focal modification to the amino acid residues. ...
Cyanobacteria are known producers of structurally diverse and potent natural products; the majority are peptides with unique modifications. Yet, there remains a huge underexplored chemodiversity from cyanobacteria. Here, we designed a linear octapeptide as a product of combinatorial peptide design inspired by the natural products from the filamentous cyanobacteria Hapalosiphon welwitschii and Leptolyngbya sp. The target peptide was synthesized via solid-phase peptide synthesis (SPPS) using fluorenylmethyloxycarbonyl-protecting group (Fmoc) strategy. Structural diversity was expanded by the substitution of unnatural amino acids to yield five analogues. The structure and sequence of the synthesized peptides were confirmed using nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). Biological activity evaluation was done; with none of the peptides showing antimicrobial or cytotoxic activities against microbial pathogens and mammalian cells, respectively. To our knowledge, this study is the first to report a combinatorial peptide design inspired by a natural product and a predicted biosynthetic product. This strategy of peptide design expands the chemistry of a known bioactive natural product with the aid of unexplored cyanobacterial biosynthetic gene clusters.
A comprehensive review of 1411 new MNPs and their structural diversity analysis and including the cyanobacterial metabolite lezoside.
A marine cyanobacterial cyclic depsipeptide, coibamide A (CbA), inhibits the mammalian protein secretory pathway by blocking the Sec61 translocon, which is an emerging drug target for cancer and other chronic diseases. In our previous structure–activity relationship study of CbA, the macrolactone ester linker was replaced with alkyl/alkenyl surrogates to provide synthetically accessible macrocyclic scaffolds. To optimize the cellular bioactivity profile of CbA analogues, novel lysine mimetics having β- and ε-methyl groups have now been designed and synthesized by a stereoselective route. A significant increase in cytotoxicity was observed upon introduction of these two methyl groups, corresponding to the d-MeAla α-methyl and MeThr β-methyl of CbA. All synthetic products retained the ability to inhibit secretion of a model Sec61 substrate. Tandem evaluation of secretory function inhibition in living cells and cytotoxicity was an effective strategy to assess the impact of structural modifications to the linker for ring closure.
