Customizably designed multibodies neutralize SARS-CoV-2 in a variant-insensitive manner

Abstract

The COVID-19 pandemic evolves constantly, requiring adaptable solutions to combat emerging SARS-CoV-2 variants. To address this, we created a pentameric scaffold based on a mammalian protein, which can be customized with up to 10 protein binding modules. This molecular scaffold spans roughly 20 nm and can simultaneously neutralize SARS-CoV-2 Spike proteins from one or multiple viral particles. Using only two different modules targeting the Spike’s RBD domain, this construct outcompetes human antibodies from vaccinated individuals’ serum and blocks in vitro cell attachment and pseudotyped virus entry. Additionally, the multibodies inhibit viral replication at low picomolar concentrations, regardless of the variant. This customizable multibody can be easily produced in procaryote systems, providing a new avenue for therapeutic development and detection devices, and contributing to preparedness against rapidly evolving pathogens.

A Rationally Designed Synthetic Antiviral Peptide Binder Targeting the Receptor-Binding Domain of SARS-CoV-2

“…In addition, recognition of the S1-subunit of SARS-CoV-2 by the host cell ACE2 receptor triggers the cleavage of the S2-subunit by the TMPRSS2, a host cell serine protease, leading to conformational alteration in S2 necessary for the fusion and subsequent entry of the virus to the host cell . Notably, several classes of biomolecules, such as antibodies, nanobodies, miniproteins, and peptides targeting the S-protein of SARS-CoV-2, have been discussed in the literature. − Further, it is evident from the cryo-EM studies that the antibodies, nanobodies, and other minimized antibody mimetics predominantly recognize the N-terminal domain (NTD) of the S-protein by binding to the RBD of the S1-subunit and neutralizing the virus. , Therefore, there is no doubt that the S1-subunit of the S-protein is collectively responsible for the infectivity of SARS-CoV-2. , Although the development of vaccines has brought relief, the virus continues to spread. Thus, it is pertinent to design, discover, and validate other classes of potential therapeutics against SARS-CoV-2.…”