Selective inhibition of ACE‐2‐interacting domain of SARS‐CoV‐2 by AIDS peptide attenuates Spike S1 associated behavioral and neuronal inflammation in in vitro and in vivo models

Abstract

AbstractBackgroundCoronavirus disease 2019 (COVID‐19) is a serious contagious illness caused by the virus strain severe acute respiratory syndrome coronavirus 2 (SARS CoV‐2). Covid‐19 patients are suffered from various brain complications, but underlying mechanism is not clear. So far, there is no proper therapeutic strategy against Covid‐19 and its implications on the brain.MethodSince SARS‐CoV‐2 binds to angiotensin‐converting enzyme 2 (ACE2) for entering into host cells, to target COVID‐19 from therapeutic angle, we designed a hexapeptide corresponding to the ACE2‐interacting domain of SARS‐CoV‐2 (AIDS) that inhibits the association between receptor‐binding domain‐containing spike S1 and ACE‐2. Initially, we have validated the effect of AIDS peptide and the its role in Spike S1 associated neuroinflammatory alteration in mouse primary glia cultures. For in vivo, recombinant spike S1 was administered Intranasally for 14 days. Wild type and mutant AIDS peptide were administered post 5 days treatment of spike S1. Post two weeks treatment, we performed several behavioral assessment and biochemical evaluationResultIncreased INOS levels and microglia activation was observed by Spike S1 treatment in mice primary microglia. AIDS peptide prominently attenuates Spike S1 associated inflammatory markers in glia cultures. Intranasal intoxication of C57/BL6 mice with recombinant SARS‐CoV‐2 spike S1 led to fever, increase in IL‐6 in lungs as well as in brain, and impairment in spatial learning memory functions and motor disabilities, mimicking some of the important symptoms of COVID‐19. Intranasal treatment with wtAIDS, but not mAIDS, peptide reduced fever, enhanced locomotor functions and cognitive and memory functions in SARS‐CoV‐2 spike S1‐intoxicated mice. Our studies show wtAIDS peptide attenuates Spike S1 inducted cytokine levels in the brain.ConclusionOur results illustrated that, selective targeting of ACE2‐to‐SARS‐CoV‐2 interaction by wtAIDS may be beneficial for COVID‐19 associated memory and learning deficits via maintaining the cytokine levels