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Aging (Albany NY) ; 12(12): 11263-11276, 2020 06 16.
Article in English | MEDLINE | ID: covidwho-601536

ABSTRACT

The outbreak of COVID-19 has now become a global pandemic that has severely impacted lives and economic stability. There is, however, no effective antiviral drug that can be used to treat COVID-19 to date. Built on the fact that SARS-CoV-2 initiates its entry into human cells by the receptor binding domain (RBD) of its spike protein binding to the angiotensin-converting enzyme 2 (hACE2), we extended a recently developed approach, EvoDesign, to design multiple peptide sequences that can competitively bind to the SARS-CoV-2 RBD to inhibit the virus from entering human cells. The protocol starts with the construction of a hybrid peptidic scaffold by linking two fragments grafted from the interface of the hACE2 protein (a.a. 22-44 and 351-357) with a linker glycine, which is followed by the redesign and refinement simulations of the peptide sequence to optimize its binding affinity to the interface of the SARS-CoV-2 RBD. The binding experiment analyses showed that the designed peptides exhibited a significantly stronger binding potency to hACE2 than the wild-type hACE2 receptor (with -53.35 vs. -46.46 EvoEF2 energy unit scores for the top designed and wild-type peptides, respectively). This study demonstrates a new avenue to utilize computationally designed peptide motifs to treat the COVID-19 disease by blocking the critical spike-RBD and hACE2 interactions.


Subject(s)
Coronavirus Infections/drug therapy , Peptides/chemical synthesis , Peptides/pharmacology , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/drug therapy , Spike Glycoprotein, Coronavirus/physiology , Amino Acid Sequence , Antiviral Agents , Binding Sites , Drug Design , Evolution, Molecular , Humans , Models, Molecular , Pandemics , Protein Binding , Protein Conformation , Virus Internalization/drug effects
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