2. Academic Validation
  3. C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein

C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein

  • J Med Chem. 2023 Aug 10;66(15):10432-10457. doi: 10.1021/acs.jmedchem.3c00576.
Marta Gargantilla 1,  Clara Francés 2,  Anmol Adhav 3,  Alicia Forcada-Nadal 3 4,  Belén Martínez-Gualda 1,  Olaia Martí-Marí 1,  María Luisa López-Redondo 3,  Roberto Melero 5,  Clara Marco-Marín 3 4,  Nadine Gougeard 3 4,  Carolina Espinosa 3,  Antonio Rubio-Del-Campo 3,  Rafael Ruiz-Partida 3,  María Del Pilar Hernández-Sierra 3,  Laura Villamayor-Belinchón 3,  Jerónimo Bravo 3,  José-Luis Llacer 3 4,  Alberto Marina 3 4,  Vicente Rubio 3 4,  Ana San-Félix 1,  Ron Geller 2,  María-Jesús Pérez-Pérez 1
Affiliations

Affiliations

  • 1 Instituto de Química Médica (IQM, CSIC), c/Juan de la Cierva 3, Madrid 28006, Spain.
  • 2 Institute for Integrative Systems Biology (I2SysBio), UV-CSIC, c/Catedrático Agustin Escardino, 9, Paterna 46980, Valencia, Spain.
  • 3 Instituto de Biomedicina de Valencia (IBV, CSIC), c/Jaime Roig 11, Valencia 46010, Spain.
  • 4 Group 739, Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER-ISCIII), Madrid 28049, Spain.
  • 5 Centro Nacional de Biotecnología (CNB, CSIC), c/Darwin 3, Madrid 28049, Spain.
PMID: 37471688 DOI: 10.1021/acs.jmedchem.3c00576
Abstract

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.

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