TY - JOUR
T1 - Targeting SARS-CoV-2 Receptor Binding Domain with Stapled Peptides
T2 - AnIn SilicoStudy
AU - de Campos, Luana Janaína
AU - Palermo, Nicholas Y.
AU - Conda-Sheridan, Martin
N1 - Funding Information:
The authors gratefully acknowledge the computing resources provided by the University of Nebraska Lincoln’s Holland Computing Center. This research was supported by startup funds from UNMC (M.C.-S.). In addition, the final assembly of the figures displayed in this paper was created with the BioRender.com website.
Publisher Copyright:
© 2021 American Chemical Society
PY - 2021/6/24
Y1 - 2021/6/24
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jpcb.1c02398
DO - 10.1021/acs.jpcb.1c02398
M3 - Article
C2 - 34114829
AN - SCOPUS:85108644996
SN - 1520-6106
VL - 125
SP - 6572
EP - 6586
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 24
ER -