AbstractTernatin and related cyclic peptides inhibit the elongation phase of protein synthesis by targeting the eukaryotic elongation factor-1α (eEF1A), a potential therapeutic vulnerability in cancer and viral infections. The cyclic peptide natural product “A3” appears to be related to ternatin, but its complete structure is unknown and only 4 of its 11 stereocenters have been assigned. Hence, A3 could be any one of 128 possible stereoisomers. Guided by the stereochemistry of ternatin and more potent structural variants, we synthesized two A3 epimers, “SR-A3” and “SS-A3”. We found that synthetic SR-A3 is indistinguishable from naturally derived A3 and potently inhibits cancer cell proliferation. Relative to SS-A3 and previously characterized ternatin variants, SR-A3 exhibits a dramatically enhanced duration of action. This increase in cellular residence time is conferred, stereospecifically, by a single β-hydroxy group attached to N-methyl leucine. SR-A3 thus exemplifies a mechanism for enhancing the pharmacological potency of cyclic peptide natural products via side-chain hydroxylation.
Bradysia hygida (Diptera, Sciaridae) presents two eukaryotic Elongation Factor 1A gene homologues: partial characterization of the eukaryotic Elongation Factor 1A-F1 gene
