Piperaquine- and Aspirin-Mediated Protective Role of HSP70 and HSP90 as Modes to Strengthen the Natural Immunity against Potent SARS-CoV-2

Since the emergence of COVID-19, the clinical manifestations are continually challenging the clinicians and scientists for the rapid development of a preventive solution of SARS-CoV-2 infections. Our hypothesis was inspired by the fact that the bats during powered flights generate heat shock responses via HSP70 and HSP90, which safeguard them from deadly viruses, including SARS-CoV-2 harbored within the bats. Therefore, we hypothesized that HSP70 and HSP90 bind with S-ACE2 and/or AngII, thereby making ACE2 less available or unavailable for SARS- CoV-2, which may enhance immunity inhibiting the cytokine storm and acute respiratory distress syndrome (ARDS). Using molecular docking approaches, molecular dynamics (MD) simulation and CYP450 metabolism studies, detailed protein-protein (S-ACE2), complex protein-protein (HSP70/90-S-ACE2), and complex protein-ligands interactions (HSP70/90-S- ACE2-ASP/PIP/HYD) were carried out to establish the most probable protective mechanism of HSPs in SARS-CoV-2 mediated ARDS. Our results showed that out of many ligands tested, piperaquine (PIP) and Aspirin (ASP) interacted quite efficiently with HSP70/90-AngII compared to the HSP70/90-S-ACE2 with the formation of a relatively stable complex having excellent DockThor scores, Delta G, and Kd values. Further, it could be predicted that ASP-inducible HSP70/90 and PIP might work through binding with the accumulated AngII due to malfunctioning of ACE2, thereby preventing the cytokine storm ARDS with fewer chances of clot formation too in COVID-19 patients. However, these purely in silico findings need to be validated in the in vitro/in vivo experimentations for further insight into the proposed preventive mechanism(s).