Targeting the SARS-CoV-2 3CLpro and NO/cGMP/PDE5 pathway in COVID-19: a commentary on PDE5 inhibitors

Abstract

Emerging in December 2019 in a local seafood market for the first time, coronavirus disease 2019 (COVID19) is not merely an infection of the respiratory tract, but rather a systemic disease of cardiovascular ground, among others [1], which is of particular interest to this commentary. To date, among the many endeavors aimed at identification of novel treatments or repurposing of long-known medications for the treatment of COVID-19, several investigations have sought to delve into the efficacy of PDE5 inhibitors including sildenafil, tadalafil and vardenafil. Used predominantly in the treatment of male erectile dysfunction and pulmonary hypertension, PDE5 inhibitors may arguably inhibit the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and prevent thromboembolism caused by inflammatory processes in COVID-19 patients. The causative viral strain was soon found to share a 79 percent sequence identity with the original SARS-CoV, that was the strain responsible for the severe acute respiratory syndrome (SARS) outbreak in 2002 [2]. With the greater proportion of the genetic sequence identity occurring in the open reading frame regions, it could be easily anticipated that the envelope S-protein and ACE2 were going to be major players in SARS-CoV-2 pathogenesis [2,3]. This hypothesis was confirmed by Zhou et. al., when they reported successful in vitro infection of ACE2-expressing human cells by SARS-CoV-2 [4]. However, this was not the only mechanism involved in the pathogenesis of the novel coronavirus, as further investigations suggested the potential role of SARS-CoV-2 3CLpro in the instigation of COVID-19 [5].