The rationale for using lopinavir is attributed to multiple studies. Lopinavir exhibited an antiviral activity against SARS-CoV-2 virus in Vero E6 cells with an estimated EC50 value of 26.63 μM [85]. Computational studies have also suggested that lopinavir may inhibit the viral main protease Mpro, perhaps by targeting its active site [86,87]. Earlier, lopinavir exhibited in vitro activity against SARS-CoV-1 and MERS-CoV [88,89,90]. It also showed beneficial effects in animal studies for the treatment of MERS-CoV [91,92]. Furthermore, there is an evidence of some clinical benefit for lopinavir/ritonavir when used with ribavirin and/or INFs against MERS-CoV and SARS-CoV [88,93,94]. Yet, coronavirus proteases, including Mpro, do not have a C2-symmetric protein architecture which is the target of lopinavir and all HIV-1 protease inhibitors. This subsequently sheds doubts on the prospect of HIV-1 aspartate protease inhibitors in treating COVID-19.