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submitted on 22.07.2020 and posted on 23.07.2020by Utsab Debnath, Varun Dewaker, Yenamandra S. Prabhakar, Parthasarathi Bhattacharyya, Amit Mandal
The infection caused by Severe Acute Respiratory Syndrome–CoronaVirus-2 (SARS-CoV-2)
resulted in a pandemic across the globe with a huge death toll. The symptoms from SARS-CoV2 appear somewhat similar to the SARS-CoV-1 infection that appeared in early 21st century but
the infectivity is far higher for the SARS-CoV-2. The virus attaches itself to exposed human
epithelial cells through the spike protein. Recently discovered crystal structure of the complex of
spike protein of SARS-CoV-2 with human angiotensin-converting enzyme 2 (ACE2) receptor
indicated that the virus binds with the host cell very strongly. We hypothesized that the
perturbation of the functionally active conformation of spike protein through the reduction of a
solvent accessible disulfide bond (Cys391-Cys525) that provides its structural architecture, may
be a feasible strategy to disintegrate the spike protein from ACE2 receptor and thereby prevent
the infection. Using in silico platform we showed that N-acetyl cysteine (NAC), a drug used as
antioxidant and mucolytic agent, binds in the close proximity of above disulfide bond. The
reduction of the disulfide bond via thiol/disulfide exchange, followed by covalent conjugation of
NAC perturbed the stereo specific orientations of interacting key residues of spike protein. This
resulted in threefold weakening in the binding affinity of spike protein with ACE2 receptor. This
opens avenues for exploring the effect of NAC in vitro, ex vivo and in vivo and on successful
observation of the similar effect as in silico, the intervention of NAC may be translated in the
pharmacoprevention and treatment of Corona virus disease 2019.