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bioRxiv · 10.1101/2020.10.06.325498

Total synthesis and biological characterization of SR-A3, a ternatin-related eEF1A inhibitor with enhanced cellular residence time

Wang, H.·Oltion, K.·Al-Khdhairawi, A. A. Q.·Weber, J.-F. F.·Taunton, J.
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Abstract

Ternatin-family cyclic peptides inhibit protein synthesis by targeting the eukaryotic elongation factor-1 (eEF1A). A potentially related cytotoxic natural product ("A3") was isolated from Aspergillus, but only 4 of its 11 stereocenters 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 enhanced residence time and rebinding kinetics, as revealed by single-molecule fluorescence imaging of elongation reactions catalyzed by eEF1A in vitro. Increased residence time - stereospecifically conferred by the unique {beta}-hydroxyl in SR-A3 - was also observed in cells. Consistent with its prolonged duration of action, thrice-weekly dosing with SR-A3 led to dramatically 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.

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Wang, H., Oltion, K., Al-Khdhairawi, A. A. Q., Weber, J.-F. F., Taunton, J.. 2020-10-08. Total synthesis and biological characterization of SR-A3, a ternatin-related eEF1A inhibitor with enhanced cellular residence time. https://doi.org/10.1101/2020.10.06.325498

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