Design and discovery of a highly potent ultralong-acting GLP-1 and glucagon co-agonist for attenuating renal fibrosis.

The role of co-agonists of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) in chronic kidney disease (CKD) remains unclear. Herein we found that GLP-1R and GCGR expression levels were lower in the kidneys of mice with CKD compared to healthy mice and were correlated with disease severity. Interestingly, GLP-1R or GCGR knockdown aggravated the progression of kidney injury in both diabetic db/db mice and non-diabetic mice undergoing unilateral ureteral obstruction (UUO). Based on the importance of GLP-1R and GCGR in CKD, we reported a novel monomeric peptide, 1907-B, with dual-agonism on both GLP-1R and GCGR. The data confirmed that 1907-B had a longer half-life than long-acting semaglutide in rats or cynomolgus monkeys (∼2-3 fold) and exhibited better therapeutic contribution to CKD than best-in-class monoagonists, semaglutide, or glucagon, in db/db mice and UUO mice. Various lock-of-function models, including selective pharmacological activation and genetic knockdown, confirmed that 1907-B's effects on ameliorating diabetic nephropathy in db/db mice, as well as inhibiting kidney fibrosis in UUO mice, were mediated through GLP-1 and glucagon signaling. These findings highlight that 1907-B, a novel GLP-1R and GCGR co-agonist, exerts multifactorial improvement in kidney injuries and is an effective and promising therapeutic option for CKD treatment.

Design of a highly potent GLP-1R and GCGR dual-agonist for recovering hepatic fibrosis.

Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) agonist with higher affinity towards GCGR, could retard the progression of liver fibrosis in various rodent models, with remarkable potency, selectivity, extended half-life and low toxicity. Four types of liver fibrosis animal models which were induced by CCl4, α-naphthyl-isothiocyanate (ANIT), bile duct ligation (BDL) and Schistosoma japonicum were used in our study. We found that TB001 treatment dose-dependently significantly attenuated liver injury and collagen accumulation in these animal models. In addition to decreased levels of extracellular matrix (ECM) accumulation during hepatic injury, activation of hepatic stellate cells was also inhibited via suppression of TGF-ß expression as well as downstream Smad signaling pathways particularly in CCl4-and S. japonicum-induced liver fibrosis. Moreover, TB001 attenuated liver fibrosis through blocking downstream activation of pro-inflammatory nuclear factor kappa B/NF-kappa-B inhibitor alpha (NFκB/IKBα) pathways as well as c-Jun N-terminal kinase (JNK)-dependent induction of hepatocyte apoptosis. Furthermore, GLP-1R and/or GCGR knock-down results represented GCGR played an important role in ameliorating CCl4-induced hepatic fibrosis. Therefore, TB001 can be used as a promising therapeutic candidate for the treatment of multiple causes of hepatic fibrosis demonstrated by our extensive pre-clinical evaluation of TB001.