Introduction
fever, mild/moderate, infection, ill, nirmatrelvir
VIRUS, CORONAVIRUS DISEASE 2019, MUTANT, INFECTION, CORONAVIRUS, SEVERE ACUTE RESPIRATORY SYNDROME, VIRAL SHEDDING, DRUG-DRUG INTERACTION
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly infectious positive-strand RNA virus causing COVID-19 (coronavirus disease 2019), has evolved through Alpha, Beta, Gamma, Delta, and Omicron mutant strains, resulting in an unabated global pandemic trend. Although quite a few COVID-19 vaccines have been used worldwide since 2021, which could significantly protect people from getting severely ill or dying, as many as hundreds of thousands of infection cases are currently reported each day.Small molecule antivirals have the advantages of easy manufacture, low cost and good accessibility.However, currently available drugs do not mean we can beat the virus efficiently. For example, nirmatrelvir must be co-packaged with ritonavir, an inhibitor of cytochrome P450 (CYP) 3A4, which would result in drug-drug interactions with many commonly used medications. In the real world for patients aged 40 to 64 years old, a retrospective observational cohort study for nirmatrelvir between January 9, 2022 and March 31, 2022 with the omicron mutant as the most prevalent in Israel, the rate of hospitalization owing to COVID-19 was 15.2 instances per 100,000 person-days among treated patients and 15.8 cases per 100,000 person-days among untreated patients, demonstrating nirmatrelvir is not effective against SARS-CoV-2 in younger adults.Herein, inspired by cutting-edge computer-aided design (CADD) techniques as well as expert knowledge, following enzymatic inhibition assay, cellular activity assay, animal investigation and clinical trial, we report the discovery of nelfinavir, an FDA approved antiretroviral drug, as a potential medication for COVID-19 with potential of preventative effect for almost all ages of people. Monkeys given nelfinavir prophylactically showed significantly lower temperatures and virus loads in nasal and anal swabs, as well as a significant reduction in virus replication in the lungs by nearly three orders of magnitude. In patients with mild/moderate COVID-19, nelfinavir could reduce the length of viral shedding by 5.5 days and the length of fever period by 3.8 days.