Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against M <sup>pro</sup> and cathepsin L
M. Sacco, Chunlong Ma, Panagiotis Lagarias, Ang Gao, Julia A. Townsend, Xiangzhi Meng, Peter H. Dube, Xiujun Zhang, Yanmei Hu, Naoya Kitamura, Brett L. Hurst, E. Bart Tarbet, Michael T. Marty, Antonios Kolocouris, Yan Xiang, Yu Chen, Jun Wang
Abstract
with calpain inhibitor II confirmed that the S1 pocket can accommodate a hydrophobic methionine side chain, challenging the idea that a hydrophilic residue is necessary at this position. The structure of calpain inhibitor XII revealed an unexpected, inverted binding pose. Together, the biochemical, computational, structural, and cellular data presented herein provide new directions for the development of dual inhibitors as SARS-CoV-2 antivirals.
Topics & Concepts
ProteaseCalpainCathepsinChemistryCathepsin LCysteine proteaseProteasesBiochemistryGlutamineCathepsin BSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2)StereochemistryEnzymeCoronavirus disease 2019 (COVID-19)Amino acidMedicineInfectious disease (medical specialty)PathologyDiseaseCalpain Protease Function and RegulationVenomous Animal Envenomation and StudiesSARS-CoV-2 and COVID-19 Research