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

  • Nat Chem. 2022 Dec;14(12):1443-1450. doi: 10.1038/s41557-022-01039-3.
Hao-Yuan Wang  1 ,  Haojun Yang  #  2 ,  Mikael Holm  #  3 ,  Harrison Tom  2 ,  Keely Oltion  1 ,  Amjad Ayad Qatran Al-Khdhairawi  4 ,  Jean-Frédéric F Weber  5 ,  Scott C Blanchard  3 ,  Davide Ruggero  1  2 ,  Jack Taunton  6
Affiliations
  • 1. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA.
  • 2. Department of Urology, University of California, San Francisco, CA, USA.
  • 3. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 4. School of Pharmacy, Faculty of Health & Medical Sciences, Taylor's University Lakeside Campus, Subang Jaya, Malaysia.
  • 5. Atta-ur-Rahman Institute for Natural Product Discovery (AuRIns), Universiti Teknologi MARA (UiTM) Selangor Branch, Bandar Puncak Alam, Malaysia.
  • 6. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA. [email protected].
  • # Contributed equally.
PMID: 36123449 DOI: 10.1038/s41557-022-01039-3
Abstract

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.