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bioRxiv · 10.1101/2025.01.13.632834

Binding Kinetics, Bias, Receptor Internalization and Effects on Insulin Secretion in vitro and in vivo of a Novel GLP-1R/GIPR Dual Agonist, HISHS-2001

Manchanda, Y.·Jones, B.·Carrat, G.·Ramchunder, Z.·Marchetti, P.·Leclerc, I.·Thennati, R.·Burade, V.·Natarajan, M.·Shahi, P.·Tomas, A.·Rutter, G. A.
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Abstract

The use of incretin analogues has emerged in recent years as an effective approach to achieve both enhanced insulin secretion and weight loss in type 2 diabetes (T2D) patients. Agonists which bind and stimulate multiple receptors have shown particular promise. However, off target effects, including nausea and diarrhoea, remain a complication of using these agents, and modified versions with optimized pharmacological profiles and/or biased signaling at the cognate receptors are increasingly sought. Here, we describe the synthesis and properties of a molecule which binds to both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors (GLP-1R and GIPR) to enhance insulin secretion. HISHS-2001 shows increased affinity at the GLP-1R, as well as a tendency towards reduced internalization and recycling at this receptor versus FDA-approved dual GLP-1R/GIPR agonist tirzepatide. HISHS-2001 also displayed significantly greater bias towards cAMP generation versus {beta}-arrestin 2 recruitment compared to tirzepatide. In contrast, Gs recruitment was lower versus tirzepatide at the GLP-1R, but higher at the GIPR. Administered to obese hyperglycaemic db/db mice, HISHS-2001 increased circulating insulin whilst lowering body weight and HbA1c with similar efficacy to tirzepatide at substantially lower doses. Thus, HISHS-2001 represents a novel dual receptor agonist with an improved pharmacological profile.

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Manchanda, Y., Jones, B., Carrat, G., Ramchunder, Z., Marchetti, P., Leclerc, I., Thennati, R., Burade, V., Natarajan, M., Shahi, P., Tomas, A., Rutter, G. A.. 2025-01-17. Binding Kinetics, Bias, Receptor Internalization and Effects on Insulin Secretion in vitro and in vivo of a Novel GLP-1R/GIPR Dual Agonist, HISHS-2001. https://doi.org/10.1101/2025.01.13.632834

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