EMD-17578

Single-particle
4.3 Å
EMD-17578 Deposition: 06/06/2023
Map released: 27/09/2023
Last modified: 16/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-17578

SARS-CoV-2 S protein S:D614G mutant in 3-down with binding site of an entry inhibitor

EMD-17578

Single-particle
4.3 Å
EMD-17578 Deposition: 06/06/2023
Map released: 27/09/2023
Last modified: 16/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Severe acute respiratory syndrome coronavirus 2
Sample: Spike glycoprotein - Severe acute respiratory syndrome coronavirus 2
Fitted models: 8p9y (Avg. Q-score: 0.117)

Deposition Authors: Adhav A , Forcada-Nadal A , Marco-Marin C, Lopez-Redondo ML, Llacer JL
C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein.
PUBMED: 37471688
DOI: doi:10.1021/acs.jmedchem.3c00576
ISSN: 0022-2623
ASTM: JMCMAR
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.