Oral antiviral CD04872SC shows promise in neutralizing COVID-19 variants, offering hope for broad-spectrum treatment

By Neha MathurApr 4 2023Reviewed by Benedette Cuffari, M.Sc.

In a recent article published in the journal Biomedicines, researchers at 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 markedly shorten the course of illness.

This exciting new small molecule drug candidate has the potential to be developed into an alternative drug treatment for [the coronavirus disease 2019] (COVID-19)."

Study: A Small Molecule That In Vitro Neutralizes Infection of SARS-CoV-2 and Its Most Infectious Variants, Delta, and Omicron. Image Credit: metamorworks / Shutterstock.com

Background

SARS-CoV-2 and its continuously emerging variants, the most recent of which include the Omicron sublineages, continue to cause infections worldwide and threaten patients of all ages. These variants have demonstrated the ease with which this lethal virus can accommodate antigenic changes in its spike (S) protein without losing its replication and immune-evading abilities. Therefore, identifying effective antivirals to combat COVID-19 is crucial.

About the study

In the present study, researchers perform in silico screening of 1,509,984 feature-rich compounds in the small molecule databases of UH Research Computing Data Core to identify top hits against the SARS-CoV-2 S glycoprotein. The top 15 molecules that disrupted the interaction between the S protein and host cell target, the angiotensin-converting enzyme 2 (ACE2) receptor, were selected, evaluated, and ranked in cell-based assays.

To this end, the researchers performed infection inhibition drug screening and cell cytotoxicity assays. Furthermore, the team used a Protein Thermal Shift assay based on differential scanning fluorimetry (DSF) utilizing a specialized fluorogenic dye to analyze stability changes of viral particles in the presence of the lead candidate CD04872SC.

Thermal shift assays quantify variations in temperatures at which a protein denatures, thereby indicating a protein’s stability under varying conditions, such as when it is attached to a drug or encounters varying pH. In the current study, a thermal shift assay was performed to demonstrate the binding between CD04872SC and the S glycoprotein of various SARS-CoV-2 variants.

Results

Molecular dynamic simulations revealed that some of the compounds from the Maybridge and ZINC libraries had favorable interactions with the ACE-2 receptor binding domain (RBD) interface. One small molecule, CD04872SC, formed the closest association in functional in vitro assays using its amide carbonyl and the backbone N of GLY169 at a resolution of 3.1 Å. This compound also established hydrophobic interactions with TYR116, TYR172, and TYR162.

CD04872SC exhibited a half-maximal effective concentration (EC₅₀) of 248 μM and was found to inhibit infection with the SARS-CoV-2 Delta and Omicron variants with EC₅₀ values of 152 μM and 308 μM, respectively. In cell cytotoxicity assays, CD04872SC showed no significant cell cytotoxicity within the tested concentrations.

Real-time melt experiments demonstrated the direct binding between CD04872SC and the S glycoprotein of each tested SARS-CoV-2 variant. The authors also noted a difference of about 3 °C in the stability of the SARS-CoV-2 viral suspensions in the presence of CD04872SC compared to its absence. Delta and Omicron exhibited similar stabilizing tendencies.

Conclusions

To summarize, the current study suggested that in striking contrast to vaccines, neutralizing small molecules could provide immediate protection against SARS-CoV-2 infection, irrespective of the age or immunity status of the individual. Such agents would have higher efficacy in high-risk populations, including immunocompromised individuals who do not adequately produce neutralizing antibodies (nAbs).

Further development of CD04872SC derivatives, including preclinical testing of their effectiveness in animal models, is still warranted to establish these agents as a potential treatment for COVID-19 and a more cost-effective substitute to expensive neutralizing mAb treatments.

This promising drug candidate lead should be developed into a family of derivatives that could be further refined, possibly leading to a more efficacious and cost-effective alternative to expensive neutralizing treatments.”