Button-Push On-Demand Synthesis for Rapid Optimization of Antiviral Peptidomimetics

Button-Push On-Demand Synthesis for Rapid Optimization of Antiviral Peptidomimetics

Journal of the American Chemical Society

10.1021/jacs.4c12834

https://doi.org/10.1021/jacs.4c12834

Duanshuai Tian, Ting Wei Tan, Ronald Toh Kuan Hai, Gan Wang, Fadhil Peer Mohamed, Zhenyang Yu, Hwee Ting Ang, Weijun Xu, Qian Wen Tan, Pearly Shuyi Ng, Choon Heng Low, Boping Liu, Perlyn Quek Zekui, Joma Kanikadu Joy, Joseph Cherian, Frankie S Mak, Jie Wu

antimicrobial agents, chemical synthesis, nitrogen compounds, peptide and proteins, peptidomimetics

30 October 2024

Tian, D., Tan, T. W., Kuan Hai, R. T., Wang, G., Mohamed, F. P., Yu, Z., Ang, H. T., Xu, W., Tan, Q. W., Ng, P. S., Low, C. H., Liu, B., Quek Zekui, P., Joy, J. K., Cherian, J., Mak, F. S., & Wu, J. (2024). Button-Push On-Demand Synthesis for Rapid Optimization of Antiviral Peptidomimetics. Journal of the American Chemical Society, 146(45), 31321–31329. https://doi.org/10.1021/jacs.4c12834

The optimization of hit compounds into drug candidates is a pivotal phase in drug discovery but often hampered by cumbersome manual synthesis of derivatives. While automated organic molecule synthesis has enhanced efficiency, safety, and cost-effectiveness, achieving fully automated multistep synthesis remains a formidable challenge due to issues such as solvent and reagent incompatibilities and the accumulation of side-products. We herein demonstrate an automated solid-phase flow platform for synthesizing α-keto-amides and nitrile peptidomimetics, guided by docking simulations, to identify potent broad-spectrum antiviral leads. A compact parallel synthesizer was built in-house, capable of producing 5 distinct molecules per cycle; 525 reactions could be finished within three months to generate 42 derivatives for a structure–activity relationship (SAR) investigation. Among these, ten derivatives exhibited promising target inhibitory activity (IC50 < 100 nM) including two with antiviral activity (EC50 < 250 nM). The platform, coupled with digital chemical recipe files, offers rapid access to a wide range of peptidomimetics, serving as a valuable reservoir for broad-spectrum antiviral candidates. This automated solid-phase flow synthesis approach expedites the generation of previously difficult complex molecular scaffolds. By integration of SPS-flow synthesis with medicinal chemistry campaign, >10-fold target inhibitory activity was achieved from a small set of derivatives, which indicates the potential to shift the paradigm of drug discovery.

Publisher Copyright

This research / project is supported by the National Research Foundation - Competitive Research Programme
Grant Reference no. : NRF-CRP25-2020RS-0002

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/jacs.4c12834.

https://oar.a-star.edu.sg/communities-collections/articles/22254

0002-7863
1520-5126

Experimental Drug Development Centre