13b-K for COVID-19

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13b-K and Nirmatrelvir Resistance Mutations of SARS-CoV-2 Main Protease: Structural, Biochemical, and Biophysical Characterization of Free Enzymes and Inhibitor Complexes, Crystals, doi:10.3390/cryst15090758
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The SARS-CoV-2 main protease (Mpro) is a well-established target for antiviral drug development One such inhibitor, nirmatrelvir, in combination with ritonavir as a booster, has already been introduced into the market, under the name Paxlovid. However, being an RNA virus, SARS-CoV-2 is prone to the emergence of resistance mutations. A number of such mutations have been characterized, although they have not yet been shown to play a significant role in clinical settings; these include S144A, E166V, H172Y, and Q189K. We recombinantly produced these mutants and studied the corresponding proteins using X-ray crystallography, enzymology, and biophysical approaches. We discuss the potential of each mutant to lead to a widespread nirmatrelvir resistance scenario. We also demonstrate that one of our own inhibitors (13b-K), while showing some degree of cross-resistance with nirmatrelvir, exhibits much higher inhibitory activity against the Mpro carrying the E166V mutation.
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