2 research outputs found
Cā2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoVā2 through Interaction with the Viral Spike (S) Protein
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
causes COVID-19, by infecting cells via the interaction of its spike
protein (S) with the primary cell receptor angiotensin-converting
enzyme (ACE2). To search for inhibitors of this key step in viral
infection, we screened an in-house library of multivalent tryptophan
derivatives. Using VSV-S pseudoparticles, we identified compound 2 as a potent entry inhibitor lacking cellular toxicity. Chemical
optimization of 2 rendered compounds 63 and 65, which also potently inhibited genuine SARS-CoV-2 cell
entry. Thermofluor and microscale thermophoresis studies revealed
their binding to S and to its isolated receptor binding domain (RBD),
interfering with the interaction with ACE2. High-resolution cryoelectron
microscopy structure of S, free or bound to 2, shed light
on cell entry inhibition mechanisms by these compounds. Overall, this
work identifies and characterizes a new class of SARS-CoV-2 entry
inhibitors with clear potential for preventing and/or fighting COVID-19
Cā2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoVā2 through Interaction with the Viral Spike (S) Protein
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
causes COVID-19, by infecting cells via the interaction of its spike
protein (S) with the primary cell receptor angiotensin-converting
enzyme (ACE2). To search for inhibitors of this key step in viral
infection, we screened an in-house library of multivalent tryptophan
derivatives. Using VSV-S pseudoparticles, we identified compound 2 as a potent entry inhibitor lacking cellular toxicity. Chemical
optimization of 2 rendered compounds 63 and 65, which also potently inhibited genuine SARS-CoV-2 cell
entry. Thermofluor and microscale thermophoresis studies revealed
their binding to S and to its isolated receptor binding domain (RBD),
interfering with the interaction with ACE2. High-resolution cryoelectron
microscopy structure of S, free or bound to 2, shed light
on cell entry inhibition mechanisms by these compounds. Overall, this
work identifies and characterizes a new class of SARS-CoV-2 entry
inhibitors with clear potential for preventing and/or fighting COVID-19