Synthesis and focused structure-activity investigation of the BB3 receptor antagonist, Bantag-1
Year: 2026
Type: preprint
Abstract: The bombesin family G protein-coupled receptor (GPCR), BB3, is an orphan GPCR linked to obesity and cancer. Limited selective chemical tools are available and only one high-affinity selective antagonist, Bantag-1, has been reported. Commercial supply of Bantag-1 has been sporadic, so we sought to develop an in-house synthesis pipeline of Bantag-1 to enable further BB3 research. Herein, we report the successful synthesis and pharmacological characterisation of Bantag-1 and a very focused structure-activity investigation. Pharmacological characterisation confirms the antagonistic properties of the synthesised peptide and provides insight into the possible contribution of the chosen counterion to storage stability. In GCaMP-based Ca2+ assays, the active synthesised peptide exhibited competitive antagonism of BAG-1-mediated BB3 signalling with a mean pA2 of 8.97, and a non-competitive antagonist profile against MK5046. Targeted structure-activity investigations further identified the C-terminal quaternary amine of Bantag-1 as a crucial moiety for antagonist activity, which is supported by our AI-based structural modelling and conventional docking of Bantag-1 with BB3. Together, we provide a practical synthetic route to the BB3 antagonist Bantag-1, establish key determinants of its activity and stability, and offer a structural framework for the rational design of next-generation BB3 chemical probes.
Source: ChemRxiv
Institutions: UNSW Sydney, University of California San Diego
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7221601474