Computational Design of Peptides to Block Binding of the SARS-CoV-2 Spike Protein to Human ACE2

ABSTRACT

The outbreak of COVID-19 has now become a global pandemic and it continues to spread rapidly worldwide, severely threatening lives and economic stability. Making the problem worse, there is no specific antiviral drug that can be used to treat COVID-19 to date. SARS-CoV-2 initiates its entry into human cells by binding to angiotensin-converting enzyme 2 (hACE2) via the receptor binding domain (RBD) of its spike protein. Therefore, molecules that can block SARS-CoV-2 from binding to hACE2 may potentially prevent the virus from entering human cells and serve as an effective antiviral drug. Based on this idea, we designed a series of peptides that can strongly bind to SARS-CoV-2 RBD in computational experiments. Specifically, we first constructed a 31-mer peptidic scaffold by linking two fragments grafted from hACE2 (a.a. 22-44 and 351-357) with a linker glycine, and then redesigned the peptide sequence to enhance its binding affinity to SARS-CoV-2 RBD. Compared with several computational studies that failed to identify that SARS-CoV-2 shows higher binding affinity for hACE2 than SARS-CoV, our protein design scoring function, EvoEF2, makes a correct identification, which is consistent with the recently reported experimental data, implying its high accuracy. The top designed peptide binders exhibited much stronger binding potency to hACE2 than the wild-type (−53.35 vs. −46.46 EvoEF2 energy unit for design and wild-type, respectively). The extensive and detailed computational analyses support the high reasonability of the designed binders, which not only recapitulated the critical native binding interactions but also introduced new favorable interactions to enhance binding. Due to the urgent situation created by COVID-19, we share these computational data to the community, which should be helpful to develop potential antiviral peptide drugs to combat this pandemic.