Introduction
The pandemic of coronavirus disease 2019 (COVID-19) caused by novel coronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has posed a serious social and economic threat world-wide by infecting over 4 million and killing 276,000 people. The real course of the disease is still not well described but mainly respiratory failure followed by cardiovascular complications with underlying inflammation and thrombus formation are rapidly emerging key threats in COVID-19.[1, 2] A “cytokine storm” or overproduction of pro-inflammatory cytokines such as interleukins (ILs) and tumor necrosis factors (TNFs) is reported in the lungs of COVID-19 patients.[3] Currently, there are no approved drugs or vaccines with proven clinical efficacy to treat or prevent COVID-19, however, the US Food and Drug Administration (FDA) approved limited emergency use for hydroxychloroquine (HCQ).[4, 5] Other drugs such as arbidol, remdesivir, and favipiravir are currently under clinical trial to treat COVID-19 with mixed reports on the efficacy of these drugs in the treatment of COVID-19.[5] There is an urgent need for an effective drug to treat and prevent COVID-19, with minimal side effects.
Limited knowledge about mechanism of infection/action of SARS-CoV-2 appears to be the major problem in identification of therapeutic target and respective drugs to treat COVID-19. However, Gordon et al., followed a comprehensive approach and cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins and identified 332 high-confidence SARS-CoV-2-human protein-protein interactions.[6] Majority of SARS-CoV-2 interacting proteins were associated with replication, epigenetic regulation and vesicle trafficking pathways.[6] In their human lung mRNA expression profile, they identified enrichment of SARS-CoV-2-interacting protein and an epigenetic regulator, histone deacetylase 2 (HDAC2), which regulates epigenetics by removing acetyl groups from histones.[6, 7] Many non-histone proteins such as transcription factors, chaperones and viral proteins are also subjected to acetylation.[7] Gordon et al., also identified 66 therapeutic targets for 69 compounds that includes Valproic Acid (VPA).[6] VPA is a FDA-approved HDAC2 inhibitor drug used to treat central nervous system disease such as epilepsy, and cancer.[8-10] VPA inhibits HDAC2 by inducing its proteasomal degradation.[9]
There are unequivocal evidence that angiotensin-converting enzyme 2 (ACE-2) receptors are the ‘entry door’ for SARS-CoV-2 to infect cells.[11, 12] ACE-2 receptors are mainly expressed on endothelial and epithelial cells.[2, 11] Endothelial cells (ECs) contribute for more than 30% of all lung cells,[13] and constitute the innermost layer of every blood vessel and respond to constantly varying hemodynamics to maintain homeostasis.[14] ECs are plastic in nature and they have the capability to lose endothelial characteristics and transition into ‘stem cell-like” mesenchymal cells, this proces is known as endothelial-to-mesenchymal transition (EndMT).[15, 16]
HCQ, which is being tested in various clinical trials against COVID-19, is an autophagy inhibitor.[17] Autophagy is a key homeostatic process, where cytosolic components are degraded and recycled through lysosomes for re-use.[17] We have previously demonstrated that inhibition of endothelial autophagy via genetic deletion of autophagy-related gene 7 (ATG7) or by pharmacologic inhibition with bafilomycin induces EndMT-like phenotypic switching in ECs.[18] Interestingly, a similar effect of VPA was also observed, where VPA induced EndMT-like phenotypic switching in ECs.[19] Given that ACE-2 is expressed basally and widely on the endothelial cells,[2, 11] we hypothesized that VPA-induced EndMT-like phenotypic switching cause reduced expression of ACE-2 and thereby would inhibit the SARS-CoV-2 rate of infection. We, for the first time show that VPA down-regulates ACE-2 expression and inhibits the expression of inflammatory cytokines in ECs. We also provide a detailed review on VPA mechanism of action and propose the plausible mechanism of VPA to protect and treat COVID-19 patients encouraging personalized therapy.