Molecular insights to the anti-COVID-19 potential of α-, β- and γ-cyclodextrins

Abstract

SARS-CoV-2 viral infection is regulated by the host cell receptors ACE2 and TMPRSS2, and therefore the effect of various natural and synthetic compounds on these receptors has recently been the subject of investigations. Cyclodextrins, naturally occurring polysaccharides derived from starch, are soluble in water and have a hydrophobic cavity at their center enabling them to accommodate small molecules and utilize them as carriers in the food, supplements, and pharmaceutical industries to improve the solubility, stability, and bioavailability of target compounds. In the current study, computational molecular simulations were used to investigate the ability of α-, β- and γ-Cyclodextrins on human cell surface receptors. Cell-based experimental approaches, including expression analyses at mRNA and protein levels and virus replication, were used to assess the effect on receptor expression and virus infection, respectively. We found that none of the three CDs could dock effectively to human cell surface receptor ACE2 and viral protease M^pro (essential for virus replication). On the other hand, α- and β-CD showed strong and stable interactions with TMPRSS2, and the expression of both ACE2 and TMPRSS2 was downregulated at the mRNA and protein levels in cyclodextrin (CD)-treated cells. A cell-based virus replication assay showed ∼20% inhibition by β- and γ-CD. Taken together, the study suggested that (i) downregulation of expression of host cell receptors may not be sufficient to inhibit virus infection (ii) activity of the receptors and virus protein M^pro may play a critical and clinically relevant role, and hence (iii) newly emerging anti-Covid-19 compounds warrant multimodal functional analyses.

Communicated by Ramaswamy H. Sarma

Keywords:

• Cyclodextrins
• SARS-CoV-2
• angiotensin-converting enzyme 2 (ACE2)
• transmembrane serine protease 2 (TMPRSS2)
• anti-virus activity

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contributions

Conceptualization - D.S, S.C.K, R.W; Bioinformatics work and formal analysis- V.K.; Experimental work - H.N.M, D.S.,. Funding acquisition - S.C.K., R.W., D.S. S.V.; Writing - review & editing V.K., S.C.K., R.W., D.S., S.V., Y.I., K.T. All authors contributed to the development of this manuscript and read and approved the final version.

Data availability statement

All data generated or analyzed during this study are included in this published article.

Additional information

Funding

This study was supported by the funds granted by AIST (Japan) and DBT (Government of India).