Avoralstat (BCX4161)

Avoralstat is an inhibitor of kallikrein, a serine protease involved in the contact activation system.¹ It inhibits kallikrein activity in isolated human plasma (EC₅₀s = 1.14-11.1 nM). Avoralstat also inhibits transmembrane serine protease 2 (TMPRSS2; IC₅₀ = 2.73 nM), a serine protease required for entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells.^2,3 It inhibits SARS-CoV-2 pseudovirus entry into Calu-3 2B4 cells (EC₅₀ = 0.7 ?M).² Avoralstat (30 mg/kg) reduces or prevents the accumulation of lung viral titers in mouse models of SARS-CoV-2 infection or prophylaxis, respectively, using Ad5-hACE2 mice that are sensitive to SARS-CoV-2 infection.

1.Cornpropst, M., Collis, P., Collier, J., et al.Safety, pharmacokinetics, and pharmacodynamics of avoralstat, an oral plasma kallikrein inhibitor: Phase 1 studyAllergy71(12)1676-1683(2016) 2.Sun, Y.J., Velez, G., Parsons, D.E., et al.Structure-based phylogeny identifies avoralstat as a TMPRSS2 inhibitor that prevents SARS-CoV-2 infection in miceJ. Clin. Invest.131(10)e147973(2021) 3.Hu, X., Shrimp, J.H., Guo, H., et al.Discovery of TMPRSS2 inhibitors from virtual screening as a potential treatment of COVID-19ACS Pharmacol. Transl. Sci.4(3)1124-1135(2021)