Abstract
Background: The recent COVID-19 (coronavirus disease 2019) pandemic triggered research on the development of new vaccines/drugs, repurposing of clinically approved drugs, and assessment of natural anti-COVID-19 compounds. Based on the gender difference in the severity of the disease, such as a higher number of men hospitalized and in intense care units, variations in sex hormones have been predicted to play a role in disease susceptibility. Cell surface receptors (Angiotensin-Converting Enzyme 2; ACE2 and a connected transmembrane protease serine 2- TMPSS2) are upregulated by androgens. Conversely, androgen antagonists have also been shown to lower ACE2 levels, implying their usefulness in COVID-19 management.
Objectives: In this study, we performed computational and cell-based assays to investigate the anti- COVID-19 potential of Withaferin-A and Caffeic acid phenethyl ester, natural compounds from Withania somnifera and honeybee propolis, respectively.
Methods: Structure-based computational approach was adopted to predict binding stability, interactions, and dynamics of the two test compounds to three target proteins (androgen receptor, ACE2, and TMPRSS2). Further, in vitro, cell-based experimental approaches were used to investigate the effect of compounds on target protein expression and SARS-CoV-2 replication.
Results: Computation and experimental analyses revealed that (i) CAPE, but not Wi-A, can act as androgen antagonist and hence inhibit the transcriptional activation function of androgen receptor, (ii) while both Wi-A and CAPE could interact with ACE2 and TMPRSS2, Wi-A showed higher binding affinity, and (iii) combination of Wi-A and CAPE (Wi-ACAPE) caused strong downregulation of ACE2 and TMPRSS2 expression and inhibition of virus infection.
Conclusion: Wi-A and CAPE possess multimodal anti-COVID-19 potential, and their combination (Wi-ACAPE) is expected to provide better activity and hence warrant further attention in the laboratory and clinic.
Keywords: Withaferin-A, Caffeic acid phenethyl ester, SARS-CoV-2, Androgen Receptor (AR), Transmembrane Protease Serine 2 (TMPRSS2), Angiotensin Converting Enzyme 2 (ACE2).
[http://dx.doi.org/10.1016/S0140-6736(20)30251-8] [PMID: 32007145]
[http://dx.doi.org/10.3390/ijms22179131] [PMID: 34502041]
[http://dx.doi.org/10.1016/j.cmi.2020.03.026]
[http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID: 32142651]
[http://dx.doi.org/10.1080/07391102.2022.2112977] [PMID: 35993530]
[PMID: 11245484]
[http://dx.doi.org/10.1016/j.eclinm.2021.100849] [PMID: 33903855]
[http://dx.doi.org/10.1016/j.isci.2021.102254] [PMID: 33681723]
[PMID: 27057074]
[http://dx.doi.org/10.1101/cshperspect.a030452] [PMID: 28389515]
[http://dx.doi.org/10.1097/PPO.0b013e318282635a] [PMID: 23337756]
[http://dx.doi.org/10.1002/(SICI)1097-0045(19990401)39:1<47::AID-PROS8>3.0.CO;2-X] [PMID: 10221266]
[http://dx.doi.org/10.1371/journal.pone.0255966] [PMID: 34618806]
[http://dx.doi.org/10.3389/fphar.2023.1049334] [PMID: 37063285]
[http://dx.doi.org/10.1002/ptr.7707] [PMID: 36562210]
[http://dx.doi.org/10.3390/cancers12051160] [PMID: 32380701]
[http://dx.doi.org/10.1007/s12192-018-0915-0] [PMID: 29869000]
[http://dx.doi.org/10.1093/gerona/gly107] [PMID: 29718136]
[http://dx.doi.org/10.1038/cddis.2017.33] [PMID: 28425984]
[http://dx.doi.org/10.1073/pnas.0500381102] [PMID: 15833816]
[http://dx.doi.org/10.1038/s41589-022-01059-7] [PMID: 35676539]
[http://dx.doi.org/10.1074/jbc.M311191200] [PMID: 14754895]
b) Desmond Molecular Dynamics System, D. E; Shaw Research: New York, NY, 2020. ;
c) Maestro-Desmond Interoperability Tools; Schrödinger Release: New York, NY, 2020.
[http://dx.doi.org/10.1021/acs.jctc.8b01026] [PMID: 30768902]
[http://dx.doi.org/10.1007/978-1-4939-2269-7_19] [PMID: 25618350]
[http://dx.doi.org/10.1093/bioinformatics/bty879] [PMID: 30329012]
[http://dx.doi.org/10.1385/ENDO:25:1:27] [PMID: 15545703]
[http://dx.doi.org/10.1210/er.2002-0032] [PMID: 15082523]
[http://dx.doi.org/10.1158/0008-5472.CAN-09-0395] [PMID: 19584279]
[http://dx.doi.org/10.1161/CIRCRESAHA.120.317015] [PMID: 32264791]
[http://dx.doi.org/10.21037/atm.2020.03.61] [PMID: 32395525]
[http://dx.doi.org/10.1021/acsptsci.0c00106] [PMID: 33062952]
[http://dx.doi.org/10.1177/03009858211058837] [PMID: 34794359]
[http://dx.doi.org/10.1016/j.phrs.2020.104859] [PMID: 32360480]
[http://dx.doi.org/10.1016/j.ijbiomac.2021.06.015] [PMID: 34118289]
[http://dx.doi.org/10.1016/j.amsu.2020.12.051] [PMID: 33489115]
[http://dx.doi.org/10.1038/srep27236] [PMID: 27250532]
[http://dx.doi.org/10.7150/jca.15170] [PMID: 27698914]
[http://dx.doi.org/10.3390/nu13082528] [PMID: 34444688]
[http://dx.doi.org/10.1002/ptr.7717] [PMID: 36757055]
[http://dx.doi.org/10.1042/BSR20212156] [PMID: 34605873]