Deconstructing SARS-CoV-2 neutralization: A modular molecular framework for computational design and comparison of antibodies and nanobodies targeting the spike RBD.

Autor: Tragni V; Department of Pharmacy-Pharmaceutical Sciences, University of Bari, Bari, Italy., Mercurio I; Department of Biosciences, Biotechnologies, Environment, University of Bari, Bari, Italy., Paoletti DP; Department of Biosciences, Biotechnologies, Environment, University of Bari, Bari, Italy., Onofrio A; Department of Pharmacy-Pharmaceutical Sciences, University of Bari, Bari, Italy., Laera L; Department of Biosciences, Biotechnologies, Environment, University of Bari, Bari, Italy., Cafferati Beltrame L; Department of Biosciences, Biotechnologies, Environment, University of Bari, Bari, Italy., Sgobba MN; Department of Biosciences, Biotechnologies, Environment, University of Bari, Bari, Italy., Guerra L; Department of Biosciences, Biotechnologies, Environment, University of Bari, Bari, Italy., Volpicella M; Department of Biosciences, Biotechnologies, Environment, University of Bari, Bari, Italy., De Grassi A; Department of Biosciences, Biotechnologies, Environment, University of Bari, Bari, Italy., Elia G; Department of Veterinary Medicine, University of Bari, Valenzano, Italy., Pierri CL; Department of Pharmacy-Pharmaceutical Sciences, University of Bari, Bari, Italy.
Jazyk: angličtina
Zdroj: Journal of medical virology [J Med Virol] 2023 Jun; Vol. 95 (6), pp. e28875.
DOI: 10.1002/jmv.28875
Abstrakt: Since 2020 the COVID-19 pandemic has led scientists to search for strategies to predict the transmissibility and virulence of new severe acute respiratory syndrome coronavirus 2 variants based on the estimation of the affinity of the spike receptor binding domain (RBD) for the human angiotensin-converting enzyme 2 (ACE2) receptor and/or neutralizing antibodies. In this context, our lab developed a computational pipeline to quickly quantify the free energy of interaction at the spike RBD/ACE2 protein-protein interface, reflecting the incidence trend observed in the transmissibility/virulence of the investigated variants. In this new study, we used our pipeline to estimate the free energy of interaction between the RBD from 10 variants, and 14 antibodies (ab), or 5 nanobodies (nb), highlighting the RBD regions preferentially targeted by the investigated ab/nb. Our structural comparative analysis and interaction energy calculations allowed us to propose the most promising RBD regions to be targeted by future ab/nb to be designed by site-directed mutagenesis of existing high-affinity ab/nb, to increase their affinity for the target RBD region, for preventing spike-RBD/ACE2 interactions and virus entry in host cells. Furthermore, we evaluated the ability of the investigated ab/nb to simultaneously interact with the three RBD located on the surface of the trimeric spike protein, which can alternatively be in up- or down- (all-3-up-, all-3-down-, 1-up-/2-down-, 2-up-/1-down-) conformations.
(© 2023 Wiley Periodicals LLC.)
Databáze: MEDLINE
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