3.2. Darunavir/Cobicistat (Prezcobix)
Darunavir (Figure 6) is another antiretroviral drug that competitively inhibits the HIV-1 aspartate protease [101,102]. In addition to the active site, it has been reported that the flexible darunavir binds to another site on the surface of the enzyme, which accounts for its resilience against potential mutations in the targeted protease [103]. Darunavir was approved in 2015 by the U.S. FDA and usually prescribed in combination with the pharmacokinetic booster cobicistat. Although structurally similar to ritonavir, cobicistat lacks antiviral activity due to the lack of the central phenyl-propanol moiety, a key structural feature of HIV protease inhibitors.
Darunavir/cobicistat is under clinical investigation for the treatment of SARS-CoV-2 infection. This is potentially attributed to darunavir ability to in vitro inhibit SARS-CoV-2 in Vero E6 cells, albeit at high concentrations (EC50 = 46.41 µM) [104]. Mechanistically, this could be because darunavir potentially inhibits 3CLpro and/or PLpro of SARS-CoV-2. The two enzymes are important for the viral glycoprotein processing. However, in another in vitro study, darunavir/cobicistat demonstrated no activity against SARS-CoV-2 at clinically relevant concentrations in Caco-2 cells [105]. Furthermore, the results from a randomized controlled trial in China showed that darunavir/cobicistat was not effective in treating COVID-19 patients [106]. Regardless, darunavir is being tried in about three trials in combination with cobicistat (NCT04252274; n = 30), ritonavir/hydroxychloroquine (NCT04435587; n = 80), ritonavir/oseltamivir, ritonavir/oseltamivir/hydroxychloroquine, or ritonavir/favipiravir/hydroxychloroquine (NCT04303299; n = 320).
TMC310911 (also known as ASC-09) (Figure 6) is structurally similar to darunavir. It is HIV-1 aspartate protease competitive inhibitor with improved antiviral activity. TMC310911 has potent activity against the wild-type HIV-1 and against an extended spectrum of recombinant HIV-1 clinical isolates, including multiple protease inhibitors-resistant strains [107]. Similar to darunavir, it was evaluated with the pharmacokinetic booster ritonavir [108]. Currently, it is being tested in two clinical trials in China in patients infected with SARS-CoV-2. It is being tested in combination with ritonavir (NCT04261907; n = 160) or oseltamivir (NCT04261270; n = 60). In a recent computational exercise, TMC-310911 was reported as a potential inhibitor of Mpro of SARS-CoV-2 [66], yet this potential is to be experimentally confirmed.