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In Silico Antibody Mutagenesis for Optimizing Its Binding to Spike Protein of Severe Acute Respiratory Syndrome Coronavirus 2.

ABSTRACT: Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic, and there are currently no FDA-approved medicines for treatment or prevention. Inspired by promising outcomes for convalescent plasma treatment, the development of antibody drugs (biologics) to block SARS-CoV-2 infection has been the focus of drug discovery, along with tremendous efforts in repurposing small-molecule drugs. In the past several months, experimentally, many human neutralizing monoclonal antibodies (mAbs) were successfully extracted from plasma of recovered COVID-19 patients. Currently, several mAbs targeting the SARS-CoV-2's spike glycoprotein (S-protein) are in clinical trials. With known atomic structures of the mAb and S-protein complex, it becomes possible to investigate in silico the molecular mechanism of mAb's binding with S-protein and to design more potent mAbs through protein mutagenesis studies, complementary to existing experimental efforts. Leveraging today's superb computing power, we propose a fully automated in silico protocol for quickly identifying possible mutations in a mAb (e.g., CB6) to enhance its binding affinity for S-protein for the design of more efficacious therapeutic mAbs.

SUBMITTER: Luan B

PROVIDER: S-EPMC7670821 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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<i>In Silico</i> Antibody Mutagenesis for Optimizing Its Binding to Spike Protein of Severe Acute Respiratory Syndrome Coronavirus 2.

Luan Binquan B Huynh Tien T

The journal of physical chemistry letters 20201104 22

Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic, and there are currently no FDA-approved medicines for treatment or prevention. Inspired by promising outcomes for convalescent plasma treatment, the development of antibody drugs (biologics) to block SARS-CoV-2 infection has been the focus of drug discovery, along with tremendous efforts in repurposing small-molecule drugs. In the past several months, experimentally, many human neutralizing monoclonal antibodies (mAbs) were succe ...[more]

PMID: 33147968

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Project description:The novel coronavirus originated in December 2019 in Hubei, China. This contagious disease named as COVID-19 resulted in a massive expansion within 6 months by spreading to more than 213 countries. Despite the availability of antiviral drugs for the treatment of various viral infections, it was concluded by the WHO that there is no medicine to treat novel CoV, SARS-CoV-2. It has been confirmed that SARS-COV-2 is the most highly virulent human coronavirus and occupies the third position following SARS and MERS with the highest mortality rate. The genetic assembly of SARS-CoV-2 is segmented into structural and non-structural proteins, of which two-thirds of the viral genome encodes non-structural proteins and the remaining genome encodes structural proteins. The most predominant structural proteins that make up SARS-CoV-2 include spike surface glycoproteins (S), membrane proteins (M), envelope proteins (E), and nucleocapsid proteins (N). This review will focus on one of the four major structural proteins in the CoV assembly, the spike, which is involved in host cell recognition and the fusion process. The monomer disintegrates into S1 and S2 subunits with the S1 domain necessitating binding of the virus to its host cell receptor and the S2 domain mediating the viral fusion. On viral infection by the host, the S protein is further cleaved by the protease enzyme to two major subdomains S1/S2. Spike is proven to be an interesting target for developing vaccines and in particular, the RBD-single chain dimer has shown initial success. The availability of small molecules and peptidic inhibitors for host cell receptors is briefly discussed. The development of new molecules and therapeutic druggable targets for SARS-CoV-2 is of global importance. Attacking the virus employing multiple targets and strategies is the best way to inhibit the virus. This article will appeal to researchers in understanding the structural and biological aspects of the S protein in the field of drug design and discovery.

Project description:BACKGROUND: Public health risks associated to infection by human coronaviruses remain considerable and vaccination is a key option for preventing the resurgence of severe acute respiratory syndrome coronavirus (SARS-CoV). We have previously reported that antibodies elicited by a SARS-CoV vaccine candidate based on recombinant, full-length SARS-CoV Spike-protein trimers, trigger infection of immune cell lines. These observations prompted us to investigate the molecular mechanisms and responses to antibody-mediated infection in human macrophages. METHODS: We have used primary human immune cells to evaluate their susceptibility to infection by SARS-CoV in the presence of anti-Spike antibodies. Fluorescence microscopy and real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) were utilized to assess occurrence and consequences of infection. To gain insight into the underlying molecular mechanism, we performed mutational analysis with a series of truncated and chimeric constructs of fragment crystallizable ? receptors (Fc?R), which bind antibody-coated pathogens. RESULTS: We show here that anti-Spike immune serum increased infection of human monocyte-derived macrophages by replication-competent SARS-CoV as well as Spike-pseudotyped lentiviral particles (SARS-CoVpp). Macrophages infected with SARS-CoV, however, did not support productive replication of the virus. Purified anti-viral IgGs, but not other soluble factor(s) from heat-inactivated mouse immune serum, were sufficient to enhance infection. Antibody-mediated infection was dependent on signaling-competent members of the human Fc?RII family, which were shown to confer susceptibility to otherwise naïve ST486 cells, as binding of immune complexes to cell surface Fc?RII was necessary but not sufficient to trigger antibody-dependent enhancement (ADE) of infection. Furthermore, only Fc?RII with intact cytoplasmic signaling domains were competent to sustain ADE of SARS-CoVpp infection, thus providing additional information on the role of downstream signaling by Fc?RII. CONCLUSIONS: These results demonstrate that human macrophages can be infected by SARS-CoV as a result of IgG-mediated ADE and indicate that this infection route requires signaling pathways activated downstream of binding to Fc?RII receptors.

Dataset Information

In Silico Antibody Mutagenesis for Optimizing Its Binding to Spike Protein of Severe Acute Respiratory Syndrome Coronavirus 2.

Publications

<i>In Silico</i> Antibody Mutagenesis for Optimizing Its Binding to Spike Protein of Severe Acute Respiratory Syndrome Coronavirus 2.

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