Researchers from the University of Houston College of Pharmacy discuss their discovery of a small molecule drug candidate that could provide immediate protection against infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and significantly shorten the course of illness in a recent article published in the journal Biomedicines.
Background
SARS-CoV-2 and its ever-emerging variants, the most recent of which include the Omicron sublineages, continue to cause infections and threaten patients of all ages around the globe. These variants show how easily this lethal virus can accept antigenic changes in its spike (S) protein while maintaining replication and immune-evasion skills. As a result, finding efficient antivirals to combat COVID-19 is critical.
Concerning the research
In this study, researchers conduct in silico screening of 1,509,984 feature-rich compounds in the UH Research Computing Data Core’s small molecule databases to find top hits against the SARS-CoV-2 S glycoprotein. In cell-based assays, the best 15 molecules that disrupted the interaction between the S protein and the host cell target, the angiotensin-converting enzyme 2 (ACE2) receptor, were chosen, assessed, and ranked.
The researchers used infection inhibition drug screening and cell cytotoxicity tests to accomplish this. Furthermore, the researchers used a Protein Thermal Shift assay based on differential scanning fluorimetry (DSF) and a specialized fluorogenic dye to examine viral particle stability changes in the presence of the top candidate CD04872SC.
Thermal shift assays measure changes in the temperature at which a protein denatures, showing the protein’s stability under different circumstances, such as when it is attached to a drug or when it is exposed to different pH levels. A thermal shift assay was used in the present research to demonstrate the binding of CD04872SC to the S glycoprotein of various SARS-CoV-2 variants.
Results
Molecular dynamic simulations showed that some compounds from the Maybridge and ZINC libraries interacted well with the ACE-2 receptor binding domain (RBD) interface. At a resolution of 3.1, one small molecule, CD04872SC, formed the closest association in functional in vitro tests using its amide carbonyl and the backbone N of GLY169. This molecule also formed hydrophobic bonds with TYR116, TYR172, and TYR162.
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CD04872SC had an EC50 of 248 M and was discovered to inhibit infection with the SARS-CoV-2 Delta and Omicron variants, which had EC50 values of 152 M and 308 M, respectively. CD04872SC revealed no significant cell cytotoxicity at the tested concentrations in cell cytotoxicity assays.
Real-time melt experiments revealed a direct interaction between CD04872SC and the S glycoprotein of each SARS-CoV-2 variant examined. The authors also discovered a 3 °C variation in the stability of SARS-CoV-2 viral suspensions in the presence of CD04872SC versus its absence. Delta and Omicron had comparable stabilizing abilities.
Conclusions
To summarize, the current research indicated that, in contrast to vaccines, neutralizing small molecules could provide immediate protection against SARS-CoV-2 infection, regardless of the individual’s age or immunity status. Such agents would be more effective in high-risk populations, such as immunocompromised individuals who do not generate enough neutralizing antibodies. (nAbs).
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More research into CD04872SC derivatives, including preclinical testing of their efficacy in animal models, is needed to establish these agents as a potential therapy for COVID-19 and a less expensive alternative to expensive neutralizing mAb treatments.
