Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS, hepatitis C and COVID-19. These protease inhibitors prevent viral replication by selectively binding to viral proteases and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles.
Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor and is used with other protease inhibitors. It may also be used in combination with other medications to treat hepatitis C and COVID-19. It is taken by mouth. Tablets of ritonavir are not bioequivalent to capsules, as the tablets may result in higher peak plasma concentrations.
Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medication. Chloroquine is also occasionally used for amebiasis that is occurring outside the intestines, rheumatoid arthritis, and lupus erythematosus. While it has not been formally studied in pregnancy, it appears safe. It was studied to treat COVID-19 early in the pandemic, but these studies were largely halted in the summer of 2020, and is not recommended for this purpose. It is taken by mouth.
Atovaquone, sold under the brand name Mepron, is an antimicrobial medication for the prevention and treatment of Pneumocystis jirovecii pneumonia (PCP).
Umifenovir, sold under the brand name Arbidol, is an antiviral medication for the treatment of influenza and COVID infections used in Russia and China. The drug is manufactured by Pharmstandard. It is not approved by the U.S. Food and Drug Administration (FDA) for the treatment or prevention of influenza.
Camostat is a serine protease inhibitor. Serine protease enzymes have a variety of functions in the body, and so camostat has a diverse range of uses. Camostat is approved in Japan for the treatment of chronic pancreatitis and postoperative reflux esophagitis. The oral proteolytic enzyme inhibitor has been on the market since 1985 under the trade name Foipan Tablets. The manufacturer is Ono Pharmaceutical. The drug is used in the treatment of some forms of cancer and is also effective against some viral infections, as well as inhibiting fibrosis in liver or kidney disease or pancreatitis.
Nafamostatmesylate (INN), a synthetic serine protease inhibitor, it is a short-acting anticoagulant, and is also used for the treatment of pancreatitis. It also has some potential antiviral and anti-cancer properties. Nafamostat is a fast-acting proteolytic inhibitor and used during hemodialysis to prevent the proteolysis of fibrinogen into fibrin. The mechanism of action of Nafamostat is as a slow tight-binding substrate, trapping the target protein in the acyl-enzyme intermediate form, resulting in apparent observed inhibition.
Masitinib is a tyrosine-kinase inhibitor used in the treatment of mast cell tumours in animals, specifically dogs. Since its introduction in November 2008 it has been distributed under the commercial name Masivet. It has been available in Europe since the second part of 2009. Masitinib has been studied for several human conditions including melanoma, multiple myeloma, gastrointestinal cancer, pancreatic cancer, Alzheimer disease, multiple sclerosis, rheumatoid arthritis, mastocytosis, amyotrophic lateral sclerosis and COVID-19.
The 3C-like protease (3CLpro) or main protease (Mpro), formally known as C30 endopeptidase or 3-chymotrypsin-like protease, is the main protease found in coronaviruses. It cleaves the coronavirus polyprotein at eleven conserved sites. It is a cysteine protease and a member of the PA clan of proteases. It has a cysteine-histidine catalytic dyad at its active site and cleaves a Gln–(Ser/Ala/Gly) peptide bond.
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19, the respiratory illness responsible for the COVID-19 pandemic. The virus previously had the provisional name 2019 novel coronavirus (2019-nCoV), and has also been called human coronavirus 2019. First identified in the city of Wuhan, Hubei, China, the World Health Organization designated the outbreak a public health emergency of international concern from January 30, 2020, to May 5, 2023. SARS‑CoV‑2 is a positive-sense single-stranded RNA virus that is contagious in humans.
Rupintrivir is a peptidomimetic antiviral drug which acts as a 3C and 3CL protease inhibitor. It was developed for the treatment of rhinoviruses, and has subsequently been investigated for the treatment of other viral diseases including those caused by picornaviruses, norovirus, and coronaviruses, such as SARS and COVID-19.
Drug repositioning is the repurposing of an approved drug for the treatment of a different disease or medical condition than that for which it was originally developed. This is one line of scientific research which is being pursued to develop safe and effective COVID-19 treatments. Other research directions include the development of a COVID-19 vaccine and convalescent plasma transfusion.
3CLpro-1 is an antiviral drug related to rupintrivir which acts as a 3CL protease inhibitor and was originally developed for the treatment of human enterovirus 71. It is one of the most potent of a large series of compounds developed as inhibitors of the viral enzyme 3CL protease, with an in vitroIC50 of 200 nM. It also shows activity against coronavirus diseases such as SARS and MERS, and is under investigation as a potential treatment agent for the viral disease COVID-19.
GC376 is a broad-spectrum antiviral medication under development by the biopharmaceutical company Anivive Lifesciences for therapeutic uses in humans and animals. Anivive licensed the exclusive worldwide patent rights to GC376 from Kansas State University. As of 2020, GC376 is being investigated as treatment for COVID-19. GC376 shows activity against many human and animal viruses including coronavirus and norovirus; the most extensive research has been multiple in vivo studies in cats treating a coronavirus which causes deadly feline infectious peritonitis. Other research supports use in porcine epidemic diarrhea virus.
GS-441524 is a nucleoside analogue antiviral drug which was developed by Gilead Sciences. It is the main plasma metabolite of the antiviral prodrug remdesivir, and has a half-life of around 24 hours in human patients. Remdesivir and GS-441524 were both found to be effective in vitro against feline coronavirus strains responsible for feline infectious peritonitis (FIP), a lethal systemic disease affecting domestic cats. Remdesivir was never tested in cats, but GS-441524 has been found to be effective treatment for FIP.
Nirmatrelvir is an antiviral medication developed by Pfizer which acts as an orally active 3C-like protease inhibitor. It is part of a nirmatrelvir/ritonavir combination used to treat COVID-19 and sold under the brand name Paxlovid.
GRL-0617 is a drug which is one of the first compounds discovered that acts as a selective small-molecule inhibitor of the protease enzyme papain-like protease (PLpro) found in some pathogenic viruses, including the coronavirus SARS-CoV-2. It has been shown to inhibit viral replication in silico and in vitro.
Bemnifosbuvir is an antiviral drug invented by Atea Pharmaceuticals and licensed to Roche for clinical development, a novel nucleotide analog prodrug originally developed for the treatment of hepatitis C. Bemnifosbuvir is the orally bioavailable hemisulfate salt of AT-511, which is metabolized in several steps to the active nucleotide triphosphate AT-9010, acting as an RNA polymerase inhibitor and thereby interfering with viral replication. Bemnifosbuvir has been researched for the treatment of coronavirus diseases such as that produced by SARS-CoV-2. It showed good results in early clinical trials but had inconsistent results at later stages, so the planned Phase 3 trials are being redesigned and results are not expected until late 2022.
Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a co-packaged medication used as a treatment for COVID‑19. It contains the antiviral medications nirmatrelvir and ritonavir and was developed by Pfizer. Both are protease inhibitors: nirmatrelvir inhibits SARS-CoV-2 main protease, while ritonavir inhibits HIV-1 protease, and is additionally a strong CYP3A inhibitor.
Ensitrelvir, sold under the brand name Xocova is an antiviral medication used as a treatment for COVID-19. It was developed by Shionogi in partnership with Hokkaido University and acts as an orally active 3C-like protease inhibitor. It is taken by mouth.
