Haitao Yang
ShanghaiTech University, China
Scientific Tracks Abstracts: Med Chem
Introduction: Coronaviruses (CoVs) infection causes various diseases in human and
animals, including severe acute respiratory syndrome (SARS) and middle east respiratory
syndrome (MERS). Human Coronavirus NL63 (HCoV-NL63) was found to cause upper
and lower respiratory tract infection worldwide. Porcine epidemic diarrhea virus (PEDV)
infects the gastrointestinal tract in feeder pigs and fattening swine and causes porcine
epidemic diarrhea. Feline infectious peritonitis virus (FIPV) leads to lethal systemic
granulomatous disease in cats. No approved specific drugs or vaccinations are available
to treat their infections.
Materials & Methods: The synthesized compounds were evaluated for the inhibition of
multiple CoV proteases and their crystal structures were determined.
Results: (1) Structural analysis of the HCoV-NL63 main protease compelx was determined,
consistent with biochemical inhibition results, reveals the molecular mechanism of
enzyme inhibition at the highly conservative substrate-recognition pocket. We show such
molecular target remains unchanged across 30 clinical isolates of HCoV-NL63 strains.
(2) We solved the structure of PEDV main protease complexed with peptidomimetic
inhibitor N3 carrying a Michael acceptor warhead, revealing atomic level interactions. We
further designed a series of 17 inhibitors with altered side groups. Inhibitors M2 and M17
demonstrated enhanced specificity against PEDV main protease. (3) We demonstrated that
zinc ion and a Michael-acceptor based peptidomimetic inhibitor synergistically inactivate
FIPV main protease. We also solved the structure of FIPV main protease complexed with
two inhibitors, delineating the structural view of dual inhibition mechanism.
Conclusion: Our study provides new insight into the pharmaceutical strategy against CoV
main proteases through design of irreversible peptidomimetic inhibitors combinded with
an adjuvant therapy to enhance the efficacy.
Haitao Yang has received his PhD in the year 2006 from Tsinghua University. His current focus is on antibiotics and antivirals Discovery in ShanghaiTech University in China. He is working as Research Professor in Shanghai Institute for Advanced Immunochemical Studies (SIAIS), at ShanghaiTech University. He has published more than 50 papers in reputed journals.
E-mail: yanght@tju.edu.cn
Medicinal Chemistry received 6627 citations as per Google Scholar report
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