**5.2 Protease inhibitors**

Lopinavir/Ritonavir is a combination therapy used as a potent inhibitor of the human immunodeficiency virus protease. Lopinavir is a protease inhibitor that inhibits the protease enzyme necessary for the virus to catalyze the cleavage of polyprotein essential for completing the viral infectious cycle. In contrast, ritonavir is used in combination with Lopinavir to inhibit cytochrome P450 and increase its half-life for a longer duration of action [66]. Lopinavir/ritonavir was also employed in the treatment of MERS. In vitro experiments have shown lopinavir/ritonavir potential in limiting replication of Coronavirus. 400 mg Lopinavir with 50 mg Ritonavir (Kaletra) is an efficacious oral anti-HIV drug [67]. A study on SARS-CoV demonstrates the inhibitory activity of Lopinavir (4 μg/mL) in plaque reduction assay.

In contrast, combination therapy of Lopinavir (400 mg) and Ritonavir (100 mg) two times a day for 14 days in SARS-CoV infected patients exhibited lessening of viral load in patients [68]. Subsequently, a randomized control trial known as the MIRACLE trial (MERS-CoV Infection Treated With A Combination of Lopinavir/ Ritonavir and Interferon Beta-1b) was started to establish the therapeutic efficacy of combination therapy of interferon β-1b along with lopinavir/ritonavir among MERS-CoV infected patients [69]. Whereas in a retrospective case–control study, treatment by a combination of Lopinavir/Ritonavir (LPV/r) and Ribavirin yielded depreciated Acute Respiratory Distress Syndrome (ARDS) as well as mortality in SARS patients [70].

Darunavir (DRV), another protease inhibitor that shares a similar mechanism for inhibiting HIV replication, like Lopinavir, is in phase III studies. In combination with Cobicistat, Darunavir showed better efficacy and tolerability among Covid-19 patients with less diarrhea and dyslipidemia and fewer adverse reaction compared with LPV/r [71].
