C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein
Marta Gargantilla, Clara Francés‐Gómez, Anmol Adhav, Alicia Forcada‐Nadal, Belén Martínez-Gualda, Olaia Martí‐Marí, Maria Lopez-Redondo, Roberto Melero, Clara Marco‐Marín, Nadine Gougeard, Carolina Espinosa, Antonio Rubio‐del‐Campo, Rafael Ruiz-Partida, María del Pilar Hernández-Sierra, Laura Villamayor-Belinchón, Jerónimo Bravo, J.L. Llacer, Alberto Marina, Vicente Rubio, Ana San‐Félix, Ron Geller, María‐Jesús Pérez‐Pérez
Abstract
High Resolution Image Download MS PowerPoint Slide 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.