Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients

Abstract

The widespread coronavirus SARS-CoV-2 has already infected over 4 million people worldwide, with a death toll over 280,000. Current treatment of COVID-19 patients relies mainly on antiviral drugs lopinavir/ritonavir, arbidol, and remdesivir, the anti-malarial drugs hydroxychloroquine and chloroquine, and traditional Chinese medicine. There are over 2,118 on-going clinical trials underway, but to date none of these drugs have consistently proven effective. Cathepsin L (CatL) is an endosomal cysteine protease. It mediates the cleavage of the S1 subunit of the coronavirus surface spike glycoprotein. This cleavage is necessary for coronavirus entry into human host cells, virus and host cell endosome membrane fusion, and viral RNA release for next round of replication. Here we summarize data regarding seven CatL-selective inhibitors that block coronavirus entry into cultured host cells and provide a mechanism to block SARS-CoV-2 infection in humans. Given the rapid growth of the SARS-CoV-2-positive population worldwide, ready-to-use CatL inhibitors should be explored as a treatment option. We identify ten US FDA-approved drugs that have CatL inhibitory activity. We provide evidence that supports the combined use of serine protease and CatL inhibitors as a possibly safer and more effective therapy than other available therapeutics to block coronavirus host cell entry and intracellular replication, without compromising the immune system.

HIV protease inhibitors saquinavir and nelfinavir are potent inhibitors of cathepsin L activity: A potential treatment for COVID-19 patients

“…Similarly, Ou and colleagues 3 show that cathepsin L inhibitor SID26681509 dramatically decreased SARS-CoV-2-S pseudovirions entry into 293/hACE2 cells, suggesting that cathepsin L is essential for priming of SARS-CoV-2 S protein in the lysosome. Indeed, this potential association has been recently proposed by Liu T et al 1 We have previously shown that the rst generation HIV protease inhibitor, saquinavir, blocks the activity of mouse cathepsin L (cathepsin V in humans) in macrophages. 4 Herein, we evaluated a possible inhibitory effect of several FDA-approved HIV protease inhibitors on the activity of cathepsin L.…”

“…The 2019 coronavirus disease pandemic (COVID-19) has mobilized efforts worldwide, and several ongoing clinical trials aimed at developing a vaccine or drug-based treatment for its control. 1 In a seminal paper, Hoffmann and colleagues demonstrated that SARS-CoV-2 employs the host cell surface receptor angiotensin-converting enzyme 2 (ACE2) for cell entry, and surface transmembrane serine protease 2 (TMPRSS2) for viral spike (S) glycoprotein priming. 2 These authors also reported that clinically proven serine protease inhibitor camostat, which is active against TMPRSS2, partially blocked SARS-2-S-driven entry into cells.…”

Risk factors for illness severity in patients with COVID-19 pneumonia: a prospective cohort study

“…Currently, SARS-CoV-2 infection has resulted in more than 80,000 laboratory-con rmed cases in China, with an overall mortality of appropriately 5% [13]. Unfortunately, despite many clinical drug trials underway, such as those for remdesivir, choloroquine, or lopinavir/ritonavir, no effective licensed drugs speci cally targeting SARS-CoV-2 are currently available [14][15][16]. The genomic sequence of SARS-CoV-2, published in 2020, shares 82% similarity with that of SARS-CoV [4,17] .…”

PT150 is a modulator of glucocorticoid and androgen receptors with antiviral activity against SARS-CoV-2

“…PT150 has unique, possibly additive effects as a direct anti-viral and as a potential modulator of the immune system. For these reasons, PT150 merits further study as a treatment for non-severe COVID-19and as a prophylactic for viral infection, alone and in combination with other potential antiviral agents, such as cathepsin-L-inhibitors, as recently suggested by Liu et al(36).…”