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PreprintCC BYChemRxiv

Synthesis and focused structure-activity investigation of the BB3 receptor antagonist, Bantag-1

  • Joshua Andrew Nillama1,2
  • Mariah R. Stavrou3,2
  • Olivia A. Clink3,2
  • Lilian Spock4,5
  • Tyler Hurlimann4,5
  • Irina Kufareva4,5
  • Nicola J. Smith3,2
  • Luke Hunter1,2
5 affiliations
  1. 1School of Chemistry
  2. 2University of New South Wales (UNSW
  3. 3School of Biomedical Sciences
  4. 4Skaggs School of Pharmacy and Pharmaceutical Sciences
  5. 5University of California San Diego
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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.

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Cite

BibTeXRIS
BibTeX
@misc{nillama2026synthesis,
  title = {{Synthesis and focused structure-activity investigation of the BB3 receptor antagonist, Bantag-1}},
  author = {Joshua Andrew Nillama and Mariah R. Stavrou and Olivia A. Clink and Lilian Spock and Tyler Hurlimann and Irina Kufareva and Nicola J. Smith and Luke Hunter},
  howpublished = {ChemRxiv},
  year = {2026},
  month = oct,
  doi = {10.26434/chemrxiv.15010357/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010357/v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Synthesis and focused structure-activity investigation of the BB3 receptor antagonist, Bantag-1
AU  - Joshua Andrew Nillama
AU  - Mariah R. Stavrou
AU  - Olivia A. Clink
AU  - Lilian Spock
AU  - Tyler Hurlimann
AU  - Irina Kufareva
AU  - Nicola J. Smith
AU  - Luke Hunter
PY  - 2026
DA  - 2026/10/13
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15010357/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010357/v1
AB  - 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.
ER  -