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Antibodies Expand the Scope of Angiotensin Receptor Pharmacology.

Publication ,  Journal Article
Skiba, MA; Sterling, SM; Rawson, S; Gilman, MSA; Xu, H; Nemeth, GR; Hurley, JD; Shen, P; Staus, DP; Kim, J; McMahon, C; Lehtinen, MK ...
Published in: bioRxiv
August 24, 2023

G protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often limited at the receptor, tissue, and cellular level. Antibodies have the potential to address these limitations but their properties as GPCR ligands remain poorly characterized. Here, using protein engineering, pharmacological assays, and structural studies, we develop maternally selective heavy chain-only antibody ("nanobody") antagonists against the angiotensin II type I receptor (AT1R) and uncover the unusual molecular basis of their receptor antagonism. We further show that our nanobodies can simultaneously bind to AT1R with specific small-molecule antagonists and demonstrate that ligand selectivity can be readily tuned. Our work illustrates that antibody fragments can exhibit rich and evolvable pharmacology, attesting to their potential as next-generation GPCR modulators.

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Published In

bioRxiv

DOI

Publication Date

August 24, 2023

Location

United States
 

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Skiba, M. A., Sterling, S. M., Rawson, S., Gilman, M. S. A., Xu, H., Nemeth, G. R., … Kruse, A. C. (2023). Antibodies Expand the Scope of Angiotensin Receptor Pharmacology. BioRxiv. https://doi.org/10.1101/2023.08.23.554128
Skiba, Meredith A., Sarah M. Sterling, Shaun Rawson, Morgan S. A. Gilman, Huixin Xu, Genevieve R. Nemeth, Joseph D. Hurley, et al. “Antibodies Expand the Scope of Angiotensin Receptor Pharmacology.BioRxiv, August 24, 2023. https://doi.org/10.1101/2023.08.23.554128.
Skiba MA, Sterling SM, Rawson S, Gilman MSA, Xu H, Nemeth GR, et al. Antibodies Expand the Scope of Angiotensin Receptor Pharmacology. bioRxiv. 2023 Aug 24;
Skiba, Meredith A., et al. “Antibodies Expand the Scope of Angiotensin Receptor Pharmacology.BioRxiv, Aug. 2023. Pubmed, doi:10.1101/2023.08.23.554128.
Skiba MA, Sterling SM, Rawson S, Gilman MSA, Xu H, Nemeth GR, Hurley JD, Shen P, Staus DP, Kim J, McMahon C, Lehtinen MK, Wingler LM, Kruse AC. Antibodies Expand the Scope of Angiotensin Receptor Pharmacology. bioRxiv. 2023 Aug 24;

Published In

bioRxiv

DOI

Publication Date

August 24, 2023

Location

United States