2. Academic Validation
  3. Crystal structure of SARS-CoV-2 nsp10-nsp16 in complex with small molecule inhibitors, SS148 and WZ16

Crystal structure of SARS-CoV-2 nsp10-nsp16 in complex with small molecule inhibitors, SS148 and WZ16

  • Protein Sci. 2022 Sep;31(9):e4395. doi: 10.1002/pro.4395.
Martin Klima 1,  Aliakbar Khalili Yazdi 2,  Fengling Li 2,  Irene Chau 2,  Taraneh Hajian 2,  Albina Bolotokova 2,  H Ümit Kaniskan 3,  Yulin Han 3,  Ke Wang 4 5,  Deyao Li 4 5,  Minkui Luo 4 5,  Jian Jin 3,  Evzen Boura 1,  Masoud Vedadi 2 6
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague 6, Czech Republic.
  • 2 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • 3 Departments of Pharmacological Sciences and Oncological Sciences, Mount Sinai Center for Therapeutics Discovery, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 4 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • 5 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
  • 6 Program of Pharmacology, Weill Cornell Medical College of Cornell University, New York, New York, USA.
PMID: 36040262 DOI: 10.1002/pro.4395
Abstract

SARS-CoV-2 nsp10-nsp16 complex is a 2'-O-methyltransferase (MTase) involved in viral RNA capping, enabling the virus to evade the immune system in humans. It has been considered a valuable target in the discovery of Antiviral therapeutics, as the RNA cap formation is crucial for viral propagation. Through cross-screening of the inhibitors that we previously reported for SARS-CoV-2 nsp14 MTase activity against nsp10-nsp16 complex, we identified two compounds (SS148 and WZ16) that also inhibited nsp16 MTase activity. To further enable the chemical optimization of these two compounds towards more potent and selective dual nsp14/nsp16 MTase inhibitors, we determined the crystal structure of nsp10-nsp16 in complex with each of SS148 and WZ16. As expected, the structures revealed the binding of both compounds to S-adenosyl-L-methionine (SAM) binding pocket of nsp16. However, our structural data along with the biochemical mechanism of action determination revealed an RNA-dependent SAM-competitive pattern of inhibition for WZ16, clearly suggesting that binding of the RNA first may help the binding of some SAM competitive inhibitors. Both compounds also showed some degree of selectivity against human protein MTases, an indication of great potential for chemical optimization towards more potent and selective inhibitors of coronavirus MTases.

Keywords

COVID-19; SARS-CoV-2; SS148; WZ16; nsp10; nsp16.

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