Year: 2020
Type: article
Abstract: Antibodies conjugated to bioactive compounds allow targeted delivery of therapeutics to cell types of choice based on that antibody's specificity. Here we develop a new type of conjugate that consists of a nanobody and a peptidic ligand for a G protein-coupled receptor (GPCR), fused via their C-termini. We address activation of parathyroid hormone receptor-1 (PTHR1) and improve the signaling activity and specificity of otherwise poorly active N-terminal peptide fragments of PTH by conjugating them to nanobodies (VHHs) that recognize PTHR1. These C-to-C conjugates show biological activity superior to that of the parent fragment peptide in vitro. In an exploratory experiment in mice, a VHH-PTH peptide conjugate showed biological activity, whereas the corresponding free peptide did not. The lead conjugate also possesses selectivity for PTHR1 superior to that of PTH(1-34). This design approach, dubbed "conjugation of ligands and antibodies for membrane proteins" (CLAMP), can yield ligands with high potency and specificity.
Source: Nature Communications
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,380
Funders: Cancer Research Institute, Massachusetts General Hospital, University of Pittsburgh, National Institutes of Health, Medical Center, University of Pittsburgh, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: Sortase-mediated protein engineering for the study of host-pathogen interactions, Hormonal Control of Calcium Metabolism, CENTER FOR SKELETAL RESEARCH, Imposing order on the family of ubiquitin-conjugating (E2) enzymes through intracellular perturbation with nanobodies, G9000155577, G9000224774, Training Program in Endocrinology
OpenAlex ID: W3022893071