The discovery and development of transmembrane serine protease 2 (TMPRSS2) inhibitors as candidate drugs for the treatment of COVID-19

Abstract

Introduction Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused the devastating pandemic named coronavirus disease 2019 (COVID-19). Unfortunately, the discovery of antiviral agents to combat COVID-19 is still an unmet need. Transmembrane serine protease 2 (TMPRSS2) is an important mediator in viral infection and thus, TMPRRS2 inhibitors may be attractive agents for COVID-19 treatment. Areas covered This review article discusses the role of TMPRSS2 in SARS-CoV-2 cell entry and summarizes the inhibitors of TMPRSS2 and their potential anti-SARS activity. Two known TMPRSS2 inhibitors, namely camostat and nafamostat, approved drugs for the treatment of pancreatitis, are under clinical trials as potential drugs against COVID-19. Expert opinion Due to the lack of the crystal structure of TMPRSS2, homology models have been developed to study the interactions of known inhibitors, including repurposed drugs, with the enzyme. However, novel TMPRSS2 inhibitors have been identified through high-throughput screening, and appropriate assays studying their in vitro activity have been set up. The discovery of TMPRSS2ʹs crystal structure will facilitate the rational design of novel inhibitors and in vivo studies and clinical trials will give a clear answer if TMPRSS2 inhibitors could be a new weapon against COVID-19.

Dynamic of Serum TWEAK Levels in Critically Ill COVID-19 Male Patients

“…On one hand, testosterone inhibits the release of pro-inflammatory cytokines, modulates the immune response, and attenuates oxidative stress and endothelial dysfunction. On the other hand, high testosterone levels might increase susceptibility and severity of COVID-19 through augmentation of TMPRSS2, which is crucial for cleaving and activation of SARS-CoV-2 spike protein during acute SARS-CoV-2 infection [63].…”

Small molecules in the treatment of COVID-19

“…The structure of TMPRSS2 is characterized by an N-terminal cytoplasmic domain, a transmembrane domain, a class A LDL receptor domain, a scavenger receptor cysteine-rich domain, and an activation domain linked to a serine protease domain via a disulfide bond. 54 , 159 , 170 Since no crystal structure of TMPRSS2 is available, repurposing or optimizing inhibitors against well-known serine proteases may facilitate the discovery of effective TMPRSS2 inhibitors against SARS-CoV-2. 170 – 172 For example, Sun et al identified structurally similar serine proteases using a structure-based phylogenetic computational tool to find potential inhibitors of TMPRSS2.…”

“… 54 , 159 , 170 Since no crystal structure of TMPRSS2 is available, repurposing or optimizing inhibitors against well-known serine proteases may facilitate the discovery of effective TMPRSS2 inhibitors against SARS-CoV-2. 170 – 172 For example, Sun et al identified structurally similar serine proteases using a structure-based phylogenetic computational tool to find potential inhibitors of TMPRSS2. 173 According to their computational results, six serine peptidases, including kallikrein-related B1, had a high structural similarity to the TMPRSS2 S1 protease domain.…”

Drugs for the prevention and treatment of COVID-19 and its complications: An update on what we learned in the past 2 years

“…It has been suggested that another TMPRSS2 inhibitor, bromhexine, presently used as a mucolytic cough suppressant, could be used to treat COVID-19 ( Habtemariam et al, 2020 ; Maggio and Corsini, 2020 ). Novel TMPRSS2 inhibitors have recently been identified using high-throughput screening ( Mantzourani et al, 2022 ), and a highly potent inhibitor has recently been well characterized ( Shapira et al, 2022 ). This compound, N-0385, is a small peptidomimetic that is active at low doses (nanomolar) and inhibits SARS-CoV-2 infection in human lung cells and in donor-derived colon organoids.…”