Potentin vitroanti-SARS-CoV-2 activity by gallinamide A and analogues via inhibition of cathepsin L

Abstract

The emergence of SARS-CoV-2 in late 2019, and the subsequent COVID-19 pandemic, has led to substantial mortality, together with mass global disruption. There is an urgent need for novel antiviral drugs for therapeutic or prophylactic application. Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is recognized as a promising drug target. The marine natural product, gallinamide A and several synthetic analogues, were identified as potent inhibitors of cathepsin L activity with IC50 values in the picomolar range. Lead molecules possessed selectivity over cathepsin B and other related human cathepsin proteases and did not exhibit inhibitory activity against viral proteases Mpro and PLpro. We demonstrate that gallinamide A and two lead analogues potently inhibit SARS-CoV-2 infection in vitro, with EC50 values in the nanomolar range, thus further highlighting the potential of cathepsin L as a COVID-19 antiviral drug target.

An Activity-Based Probe for Cathepsin K Imaging with Excellent Potency and Selectivity

“…It acts as an irreversible inhibitor of cathepsin L and was highly potent against parasite cathepsin L-like proteases cruzain and falcipain . Cathepsin L inhibition by gallinamide A was causative for a reduced SARS-CoV-2 infection in vitro . Thalassospiramide C, produced by marine bacteria, contains the acrylamide within the 12-membered depsipeptide cycle.…”

“…18 Cathepsin L inhibition by gallinamide A was causative for a reduced SARS-CoV-2 infection in vitro. 19 Thalassospiramide C, produced by marine bacteria, contains the acrylamide within the 12-membered depsipeptide cycle. An X-ray crystal structure of its Ndesmethyl derivative (compound 4 in Figure 1; PDB ID: 6HGY) in the active site of cathepsin K corroborated the nucleophilic attack of the active-site cysteine on the β position of the Michael acceptor part.…”

SARS-CoV-2 Infects Hamster Testes

“…SARS-CoV-2 has been shown to enter cells through one of two pathways, which require, in addition to its receptor angiotensin-converting enzyme 2 (ACE2), either cathepsins or transmembrane protease serine 2 (TMPRSS2) to efficiently complete its entry step [ 30 , 31 , 32 , 33 ]. Qi and colleagues analyzed expression of ACE2 and TMPRSS2 and found that cell types in the testes that express both proteins include spermatogonia, spermatogonia stem cells, peritubular myoid cells, and testes somatic cells [ 34 ].…”

First Total Synthesis and Structure–Activity Relationship of Iheyamide A, an Antitrypanosomal Linear Peptide Isolated from a Dapis sp. Marine Cyanobacterium

“…To date, several bioactive natural products have been reported that possess a pyrrolinone ring, such as belamide A, caldoramide, and dolastatin 15 . Among them, gallinamide A is one of the best studied and has shown several attractive biological activities, such as to Chagas disease and SARS-CoV-2 infection . The research presented herein provides new insights into this interesting class of natural products.…”