2023-08-04 14:45:53
In the initial stages of the replication cycle of SARS-CoV-2, the causative agent of COVID-19, interaction occurs between the viral S protein and the primary receptor of the host cell, angiotensin-converting enzyme 2 (ACE2). , followed by internalization of the virus. These initial stages of the infection are especially attractive in the search for antivirals, since compounds that act at this level could be used both therapeutically and prophylaxis.
Some researchers from the Institute of Medicinal Chemistry (IQM), attached to the Higher Council for Scientific Research (CSIC), the Institute of Integrative Systems Biology (I2SysBio), of the CSIC and the University of Valencia (UV) and the Institute of Biomedicine of Valencia (IBV) of the CSIC, members of the Interdisciplinary Thematic Platform (PTI) Global Health, all these entities in Spain, have identified and characterized a new class of antivirals against SARS-CoV-2. These work by blocking the entry of the virus into the host cell through its interaction with the spike protein (S protein).
Previous studies carried out by IQM researchers indicated that tryptophan derivatives (an essential amino acid) are good candidates for use as antivirals, since they have the ability to inhibit the entry of different viruses and have low cytotoxicity.
In the new study, screening tests have been carried out from a collection of different multivalent derivatives of tryptophan, with possible antiviral activity. By using VSV (vesicular stomatitis virus) pseudoparticles, capable of expressing the S protein of SARS-CoV-2, the interaction of the compounds in the collection with the viral spike protein was evaluated.
After this screening process, the research team, headed by Marta Gargantilla from the IQM, has identified a hit compound, a molecule with the sought-after pharmacological activity, which has been the subject of study and optimization, obtaining an active C‑2 thiophenyltryptophan trimer. and useful for more advanced clinical studies. Among the analyzes to which this compound has been subjected, the validation of the antiviral activity against genuine SARS-CoV-2 is included. In addition, other analyzes with Thermofluor and microscale thermophoresis demonstrate the interaction of these compounds with the RBD receptor binding domain of the S protein, preventing the interaction with ACE2.
Photograph captured by an electron microscope and then processed showing a human cell infected with viral particles of the SARS-CoV-2 coronavirus, the culprit of COVID-19, shown in yellow. (Image: NIAID/NIH)
Finally, the researchers used high-resolution cryoelectronic microscopy to characterize the structure of the S protein in the presence and absence of the hit compound tested, which has contributed to clarifying the mechanism of action of this new class of antiviral compounds.
The study is titled “C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein”. And it is published in the academic journal Journal of Medicinal Chemistry. (Source: CSIC)
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