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.