AI Article Synopsis
- The main protease (M) of SARS-CoV-2 is crucial for the virus's maturation and is the target of the COVID-19 treatment Paxlovid, but there's a pressing need to find new inhibitors due to potential viral resistance.
- The study utilized advanced techniques like native mass spectrometry and UV photodissociation to analyze the structure of M and how it interacts with potential covalent inhibitors.
- Results indicated that certain inhibitors enhance the stability of M by creating dimeric complexes with higher melting temperatures and lower charge states, providing valuable insights into how these inhibitors work.
Article Abstract
The main protease (M) of SARS-CoV-2 is an essential enzyme for coronaviral maturation and is the target of Paxlovid, which is currently the standard-of-care treatment for COVID-19. There remains a need to identify new inhibitors of M as viral resistance to Paxlovid emerges. Here, we report the use of native mass spectrometry coupled with 193 nm ultraviolet photodissociation (UVPD) and integrated with other biophysical tools to structurally characterize M and its interactions with potential covalent inhibitors. The overall energy landscape was obtained using variable temperature nanoelectrospray ionization (vT-nESI), thus providing quantitative evaluation of inhibitor binding on the stability of M. Thermodynamic parameters extracted from van't Hoff plots revealed that the dimeric complexes containing each inhibitor showed enhanced stability through increased melting temperatures as well as overall lower average charge states, giving insight into the basis for inhibition mechanisms.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11499983 | PMC |
| http://dx.doi.org/10.1021/acs.analchem.4c02311 | DOI Listing |
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