Unveiling novel pharmacophores and hit compounds for the development of anti-virals to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Publication date: Jul 04, 2025

The respiratory infection COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which continues to spread worldwide causing more than a million deaths yearly. Despite the rapid development of vaccines for prevention, a critical need remains for therapeutic agents to combat the established infection. With this goal in mind, we conducted a target- (SARS-CoV-2 chemotrypsin-like protease, M) and phenotypic-based screening of a subset of compounds from our in-house chemo-library. The selected compounds have been previously studied in different diseases’ models. About 45 % of the analyzed compounds displayed inhibitory activity against M in the low μM range. Additionally, 3 out of 26 tested compounds (11 %) against SARS-CoV-2 displayed true anti-viral activity and (SI > 2). One of them belongs to the chloroquine-heterocycle chemotype, which was previously reported to hold anti-SARS-CoV-2. The remaining two novel hits belong to the polyhedral-boron system, metallacarborane and dicarba-closo-dodecaborane chemotypes, which have not been previously reported for this anti-viral activity. In addition to targeting M, the chloroquine- and the metallacarborane-derivative, but not the dicarba-closo-dodecaborane, also inhibited the papain-like protease of SARS-CoV-2.

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