Nanobody-based conjugates targeting small molecule-binding GPCRs and exhibiting logic-gated signaling.

ABSTRACT: G protein-coupled receptors (GPCRs) are the largest family of plasma membrane embedded signaling proteins. These receptors are involved in a wide array of physiological processes, marking them as attractive targets for drug development. Bitopic ligands, which are comprised of a pharmacophore that targets the receptor orthosteric site and a linked moiety that binds to a separate site, have considerable potential for addressing GPCR function. Here, we report the synthesis and evaluation of novel bitopic conjugates consisting of a small molecule pharmacophore that activates the adenosine A2A receptor (A2AR) linked to antibody fragments (nanobodies, Nbs). This approach leverages the high affinity and specificity binding of Nbs to non-orthosteric sites on engineered A2AR variants to provide bit

SUBMITTER: Sachdev S 

PROVIDER: S-EPMC12478371 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature