Volume 16 of Issue 738 | Science translational medicine
Authors: Westberg M, Su Y, Zou X, Huang P, Rustagi A, Garhyan J, Patel PB, Fernandez D, Wu Y, Hao C, Lo CW, Karim M, Ning L, Beck A, Saenkham-Huntsinger P, Tat V, Drelich A, Peng BH, Einav S, Tseng CK, Blish C, Lin MZ
Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M) 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 M 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.
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Seminars in immunology
Authors: Peluso MJ, Abdel-Mohsen M, Henrich TJ, Roan NR
Nature communications
Authors: Park HJ, Gonsalves GS, Tan ST, Kelly JD, Rutherford GW, Wachter RM, Schechter R, Paltiel AD, Lo NC
Nature communications
Authors: Jaumdally S, Tomasicchio M, Pooran A, Esmail A, Kotze A, Meier S, Wilson L, Oelofse S, van der Merwe C, Roomaney A, Davids M, Suliman T, Joseph R, Perumal T, Scott A, Shaw M, Preiser W, Williamson C, Goga A, Mayne E, Gray G, Moore P, Sigal A, Limberis J, Metcalfe J, Dheda K
Annals of internal medicine
Authors: Paules CI, Wang J, Tomashek KM, Bonnett T, Singh K, Marconi VC, Davey RT, Lye DC, Dodd LE, Yang OO, Benson CA, Deye GA, Doernberg SB, Hynes NA, Grossberg R, Wolfe CR, Nayak SU, Short WR, Voell J, Potter GE, Rapaka RR
Critical care (London, England)
Authors: Alipanah-Lechner N, Hurst-Hopf J, Delucchi K, Swigart L, Willmore A, LaCombe B, Dewar R, Lane HC, Lallemand P, Liu KD, Esserman L, Matthay MA, Calfee CS, I-SPY COVID Consortium
medRxiv : the preprint server for health sciences
Authors: Van Phan H, Tsitsiklis A, Maguire CP, Haddad EK, Becker PM, Kim-Schulze S, Lee B, Chen J, Hoch A, Pickering H, Van Zalm P, Altman MC, Augustine AD, Calfee CS, Bosinger S, Cairns C, Eckalbar W, Guan L, Jayavelu ND, Kleinstein SH, Krammer F, Maecker HT, Ozonoff A, Peters B, Rouphael N, IMPACC Network, Montgomery RR, Reed E, Schaenman J, Steen H, Levy O, Diray-Arce J, Langelier CR
PloS one
Authors: Moloney K, Lamprea Montealegre JA, Busch Isaksen TM, Kennedy M, Archer M, Contreras C, Iyaz D, Randazza J, Silva J, Errett NA
Scientific Reports
Authors: Houston PD, Vittinghoff E, Marcus GM
PloS one
Authors: Cozen AE, Carton T, Hamad R, Kornak J, Faulkner Modrow M, Peyser ND, Park S, Orozco JH, Brandner M, O'Brien EC, Djibo DA, McMahill-Walraven CN, Isasi CR, Beatty AL, Olgin JE, Marcus GM, Pletcher MJ
