Antibodies Expand the Scope of Angiotensin Receptor Pharmacology.

Autor:	Skiba MA; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA., Sterling SM; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA., Rawson S; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA., Gilman MSA; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA., Xu H; Department of Pathology, Boston Children's Hospital, Boston, MA, 02115, USA., Nemeth GR; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA., Hurley JD; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA., Shen P; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, 02138, USA., Staus DP; Department of Medicine and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA., Kim J; Department of Medicine and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA., McMahon C; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA., Lehtinen MK; Department of Pathology, Boston Children's Hospital, Boston, MA, 02115, USA., Wingler LM; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA., Kruse AC; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Aug 24. Date of Electronic Publication: 2023 Aug 24.
DOI:	10.1101/2023.08.23.554128
Abstrakt:	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. Competing Interests: Competing Interests A.C.K., C.M., L.W., D.P.S., and M.A.S., are co-inventors on patent application for AT1R blocking nanobodies. A.C.K. is a cofounder and consultant for biotechnology companies Tectonic Therapeutic and Seismic Therapeutic, and also for the Institute for Protein Innovation, a nonprofit research institute. L.M.W. is a scientific advisor for Septerna. D.P.S. is a Septerna employee. C.M. is a Sanofi employee.
Databáze:	MEDLINE
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