TY - JOUR
T1 - An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations
AU - Westberg, Michael
AU - Su, Yichi
AU - Zou, Xinzhi
AU - Huang, Pinghan
AU - Rustagi, Arjun
AU - Garhyan, Jaishree
AU - Patel, Puja Bhavesh
AU - Fernandez, Daniel
AU - Wu, Yan
AU - Hao, Chenzhou
AU - Lo, Chieh Wen
AU - Karim, Marwah
AU - Ning, Lin
AU - Beck, Aimee
AU - Saenkham-Huntsinger, Panatda
AU - Tat, Vivian
AU - Drelich, Aleksandra
AU - Peng, Bi Hung
AU - Einav, Shirit
AU - Tseng, Chien Te K.
AU - Blish, Catherine
AU - Lin, Michael Z.
N1 - Publisher Copyright:
© 2024 American Association for the Advancement of Science. All rights reserved.
PY - 2024/3/13
Y1 - 2024/3/13
N2 - Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized that the covalent hepatitis C virus protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 Mpro more efficiently than existing drugs. Performing structure-guided modifications of BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, oral pharmacokinetics, and therapeutic efficacy similar or superior to those of NTV. A crucial feature of ML2006a4 is a derivatization of the ketoamide reactive group that improves cell permeability and oral bioavailability. Last, ML2006a4 was found to be less sensitive to several mutations that cause resistance to NTV or ETV and occur in the natural SARS-CoV-2 population. Thus, anticipatory design can preemptively address potential resistance mechanisms to expand future treatment options against coronavirus variants.
AB - Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized that the covalent hepatitis C virus protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 Mpro more efficiently than existing drugs. Performing structure-guided modifications of BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, oral pharmacokinetics, and therapeutic efficacy similar or superior to those of NTV. A crucial feature of ML2006a4 is a derivatization of the ketoamide reactive group that improves cell permeability and oral bioavailability. Last, ML2006a4 was found to be less sensitive to several mutations that cause resistance to NTV or ETV and occur in the natural SARS-CoV-2 population. Thus, anticipatory design can preemptively address potential resistance mechanisms to expand future treatment options against coronavirus variants.
UR - http://www.scopus.com/inward/record.url?scp=85187731153&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.adi0979
DO - 10.1126/scitranslmed.adi0979
M3 - Journal article
C2 - 38478629
AN - SCOPUS:85187731153
SN - 1946-6234
VL - 16
JO - Science translational medicine
JF - Science translational medicine
IS - 738
M1 - eadi0979
ER -