New tools from chemistry and antibodies to address receptor function

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

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Abstract

Cell surface receptors are a principal target of compounds used in therapeutic applications. One fundamental challenge of pharmaceutical development is identifying compounds that are highly specific for their target of interest, exhibit high potency and efficacy, and induce receptor responses with desirable characteristics. The broad goal of this project is to develop new tools to understand and modulate the function of protein receptors found at the surface of mammalian cells. These tools will allow us stimulate biological responses from receptors involved in beneficial processes and block responses from those involved in detrimental processes. We focus on a superfamily of cell surface proteins called G protein-coupled receptors (GPCRs), the largest group of cell surface proteins, with a specific interest in receptors involved in diabetes, osteoporosis, and inflammation. In this project we use single domain antibodies (nanobodies), small proteins with unique properties derived from the immune system of camels, alpacas, and llamas, to address these challenges. We use chemical methods to functionalize nanobodies with synthetic moieties such as peptides with non-natural amino acids and small molecules that allow for precise targeting and well-controlled modulation of targeted receptors. Using this methodology we have developed new varieties of nanobody-based conjugates for targeting previously unaddressed receptors such as adenosine-binding targets and tachykinin receptor-1. We have also developed a new approach that allows nanobodies to form a covalent (irreversible) bond with their target, which has implications for designing new long-acting therapeutics. Using assays with mammalian cells we have shown that these new tools and approaches provide compounds with new and useful properties such as high specificity and prolonged biological responses, which could be useful in designing new tool compounds or therapeutics.