Computational Design of Stapled Peptide Inhibitor against SARS-CoV-2
Receptor Binding Domain
Abstract
Since its first detection in 2019, the Severe Acute Respiratory Syndrome
Coronavirus 2 (SARS-CoV-2) has been the cause of millions of deaths
worldwide. Despite the development and administration of different
vaccines, the situation is still worrisome as the virus is constantly
mutating to produce newer variants some of which are highly infectious.
This raises an urgent requirement to understand the infection mechanism
and thereby design therapeutic-based treatment for COVID-19. The gateway
of the virus to the host cell is mediated by the binding of the Receptor
Binding Domain (RBD) of the virus spike protein to the
Angiotensin-Converting Enzyme 2 (ACE2) of the human cell. Therefore, the
RBD of SARS-CoV-2 can be used as a target to design therapeutics. The α1
helix of ACE2 which forms direct contact with the RBD surface has been
used as a template in the current study to design stapled peptide
therapeutics. Using computer simulation, the mechanism and
thermodynamics of the binding of six stapled peptides with RBD have been
estimated. Among these, the one with two lactam stapling agents has
shown binding affinity, sufficient to overcome RBD-ACE2 binding.
Analyses of the mechanistic detail reveal that a reorganization of amino
acids at the RBD-ACE2 interface produces favorable enthalpy of binding
whereas conformational restriction of the free peptide reduces the loss
in entropy to result in higher binding affinity. The understanding of
the relation of the nature of the stapling agent with their binding
affinity opens up the avenue to explore stapled peptides as therapeutic
against SARS-CoV-2.