Synthesis and single-molecule imaging reveal stereospecific enhancement of binding kinetics by the antitumour eEF1A antagonist SR-A3

• Published in: Nature Chemistry
• Main Author: Wang H.-Y.; Yang H.; Holm M.; Tom H.; Oltion K.; Al-Khdhairawi A.A.Q.; Weber J.-F.F.; Blanchard S.C.; Ruggero D.; Taunton J.
• Format: Article
• Language: English
• Published: Nature Research 2022
• Online Access: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85138252320&doi=10.1038%2fs41557-022-01039-3&partnerID=40&md5=44c9a7f870825e1eb27788b958447242

Ternatin-family cyclic peptides inhibit protein synthesis by targeting the eukaryotic elongation factor-1α. A potentially related cytotoxic natural product (‘A3’) was isolated from Aspergillus, but only 4 of its 11 stereocentres could be assigned. Here, we synthesized SR-A3 and SS-A3—two out of 128 possible A3 epimers—and discovered that synthetic SR-A3 is indistinguishable from naturally derived A3. Relative to SS-A3, SR-A3 exhibits an enhanced residence time and rebinding kinetics, as revealed by single-molecule fluorescence imaging of elongation reactions catalysed by eukaryotic elongation factor-1α in vitro. An increased residence time—stereospecifically conferred by the unique β-hydroxyl in SR-A3—was also observed in cells. Consistent with its prolonged duration of action, thrice-weekly dosing with SR-A3 led to a reduced tumour burden and increased survival in an aggressive Myc-driven mouse lymphoma model. Our results demonstrate the potential of SR-A3 as a cancer therapeutic and exemplify an evolutionary mechanism for enhancing cyclic peptide binding kinetics via stereospecific side-chain hydroxylation. [Figure not available: see fulltext.] © 2022, The Author(s), under exclusive licence to Springer Nature Limited.