Post by Nadica (She/Her) on Oct 26, 2024 2:48:45 GMT
Replication Capacity and Susceptibility of Nirmatrelvir-Resistant Mutants to Next-Generation Mpro Inhibitors in a SARS-CoV-2 Replicon System - Published Oct 17, 2024
Highlights
•Mpro mutations have variable effects on SARS-CoV-2 RNA replication.
•ML2006a4 suppresses a wide range of nirmatrelvir-resistant Mpro mutants.
•Ensitrelvir surpasses Nirmatrelvir vs. E166V but not S144A, E166A, and L167F mutants.
•Ibuzatrelvir surpasses Nirmatrelvir vs. E166A but not other Mpro mutants.
Abstract
There is an ongoing need to expand the anti-SARS-CoV-2 armamentarium to include agents capable of suppressing replication of drug-resistant mutants emerging during monotherapy with approved direct-acting antivirals. Using a subgenomic SARS-CoV-2 replicon system, we studied the RNA replication capacity of nirmatrelvir (NTV)-resistant mutants and their susceptibility to next-generation Mpro inhibitors, including ibuzatrelvir (ITV), ensitrelvir (ETV), and ML2006a4. Our findings revealed that E166V Mpro mutants reduced viral RNA replication, whereas other Mpro mutations retained or increased the replication capacity, suggesting the potential of the latter to dominate under NTV selective pressure. Except for having an advantage against E166A mutants, ITV largely showed the same mutational sensitivity as NTV. ETV was more effective than NTV against E166V mutants but less effective against S144A, E166A, and L167F mutants. ML2006a4 demonstrated the most effective suppression across most mutants (S144A, E166V, S144A+L50F, E166A/V+L50F, L167F+L50F, and E166A+L167F+L50F). Thus, ML2006a4 represents an attractive investigational candidate against clinically relevant NTV-resistant SARS-CoV-2 mutants.
Keywords
SARS-CoV-2 replication,Mpro inhibitors resistance, Nirmatrelvir, Ibuzatrelvir, Ensitrelvir, ML2006a4
Highlights
•Mpro mutations have variable effects on SARS-CoV-2 RNA replication.
•ML2006a4 suppresses a wide range of nirmatrelvir-resistant Mpro mutants.
•Ensitrelvir surpasses Nirmatrelvir vs. E166V but not S144A, E166A, and L167F mutants.
•Ibuzatrelvir surpasses Nirmatrelvir vs. E166A but not other Mpro mutants.
Abstract
There is an ongoing need to expand the anti-SARS-CoV-2 armamentarium to include agents capable of suppressing replication of drug-resistant mutants emerging during monotherapy with approved direct-acting antivirals. Using a subgenomic SARS-CoV-2 replicon system, we studied the RNA replication capacity of nirmatrelvir (NTV)-resistant mutants and their susceptibility to next-generation Mpro inhibitors, including ibuzatrelvir (ITV), ensitrelvir (ETV), and ML2006a4. Our findings revealed that E166V Mpro mutants reduced viral RNA replication, whereas other Mpro mutations retained or increased the replication capacity, suggesting the potential of the latter to dominate under NTV selective pressure. Except for having an advantage against E166A mutants, ITV largely showed the same mutational sensitivity as NTV. ETV was more effective than NTV against E166V mutants but less effective against S144A, E166A, and L167F mutants. ML2006a4 demonstrated the most effective suppression across most mutants (S144A, E166V, S144A+L50F, E166A/V+L50F, L167F+L50F, and E166A+L167F+L50F). Thus, ML2006a4 represents an attractive investigational candidate against clinically relevant NTV-resistant SARS-CoV-2 mutants.
Keywords
SARS-CoV-2 replication,Mpro inhibitors resistance, Nirmatrelvir, Ibuzatrelvir, Ensitrelvir, ML2006a4