JenKem Technology presented a research poster at the TIDES 2025 meeting titled “Dual-Arm Fatty Acid Conjugated Peptides: Structural Optimization and Advantage Exploration”.
Inspired by studies demonstrating that dual-arm fatty acid conjugation could enhance albumin binding and prolong pharmacokinetics, we synthesized novel Tirzepatide analogs JK-1246R-011 and JK-1246R-012 via conjugation of dual-arm fatty acid side chains to its peptide backbone. We sought to evaluate these analogs for improved stability, bioactivity, and in vivo efficacy.
Mass spectrometry confirmed the successful conjugation of dual-arm fatty acids to the Tirzepatide peptide backbone, with molecular weights of 5395.32 Da (JK-1246R-011) and 5339.21 Da (JK-1246R-012). HPLC analysis showed purities of 98.33% and 97.82%, respectively. In vitro activity assays revealed that JK-1246R 011 exhibited ~1.5-fold lower GIPR and ~3.6-fold lower GLP-1R activation than Tirzepatide, while JK-1246R-012 maintained equivalent GIPR activity and ~2.1-fold lower GLP-1R activity. Surface plasmon resonance (SPR) analysis showed JK-1246R-012 had a stronger albumin binding affinity (KD = 1.98 × 10⁻⁸ M) than Tirzepatide (2.18 × 10⁻⁸ M). In vivo pharmacodynamic studies in C57BL/6J mice demonstrated superior glucose tolerance at 72 hours post-dose for both analogs-42% (JK-1246R-011) and 44% (JK-1246R-012) improvements over Tirzepatide (AUC, n = 6). JK-1246R-012 retained an 18% advantage even at 144 hours post administration.
Dual-arm fatty acid conjugation significantly improves the pharmacokinetic and pharmacodynamic profiles of Tirzepatide analogs. JK-1246R-011 and JK-1246R-012 demonstrate enhanced albumin binding and sustained glucose-lowering effects, supporting their potential as next-generation long-acting GLP-1 therapeutics. Future research will explore the application of this conjugation strategy to other peptide drug candidates for prolonged action.