Researchers from the Higher Council for Scientific Research (CSIC in Spanish) have identified and characterized a new class of antivirals against SARS-CoV-2 that act by blocking the entry of the virus into the host cell through its interaction with the ‘spike’ protein (S protein).

The work has been carried out by researchers from the Higher Council for Scientific Research at the Institute of Medicinal Chemistry (IQM-CSIC), the Institute of Integrative Systems Biology (I2SysBio-CSIC-UV) and the Institute of Biomedicine of Valencia (IBV -CSIC), members of the Interdisciplinary Thematic Platform (PTI) Global Health, and has been the result of the interdisciplinary collaboration of the authors within the framework of the ‘PTI+ Global Health’, which has been published in the Journal of Medicinal Chemistry.

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.

According to the CSIC, 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.

Previous studies carried out by IQM-CSIC 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 this 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 scientists have identified a hit compound, a molecule with the sought-after pharmacological activity, which has been studied and optimized, obtaining a thiophenyltryptophan C-2 trimer, active and useful for more advanced clinical studies.

Among the studies 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.

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.

Source: dpa

(Reference image source: Unsplash, in collaboration with Getty Images)

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