posted on 2021-06-11, 16:06authored byLuana
Janaína de Campos, Nicholas Y. Palermo, Martin Conda-Sheridan
Severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) has
evolved into a pandemic of unprecedented scale. This coronavirus enters
cells by the interaction of the receptor binding domain (RBD) with
the human angiotensin-converting enzyme 2 receptor (hACE2). In this
study, we employed a rational structure-based design to propose 22-mer
stapled peptides using the structure of the hACE2 α1 helix as
a template. These peptides were designed to retain the α-helical
character of the natural structure, to enhance binding affinity, and
to display a better solubility profile compared to other designed
peptides available in the literature. We employed different docking
strategies (PATCHDOCK and ZDOCK) followed by a double-step refinement
process (FIBERDOCK) to rank our peptides, followed by stability analysis/evaluation
of the interaction profile of the best docking predictions using a
500 ns molecular dynamics (MD) simulation, and a further binding affinity
analysis by molecular mechanics with generalized Born and surface
area (MM/GBSA) method. Our most promising stapled peptides presented
a stable profile and could retain important interactions with the
RBD in the presence of the E484K RBD mutation. We predict that these
peptides can bind to the viral RBD with similar potency to the control
NYBSP-4 (a 30-mer experimentally proven peptide inhibitor). Furthermore,
our study provides valuable information for the rational design of
double-stapled peptide as inhibitors of SARS-CoV-2 infection.