Novel Muscle-Homing Peptide FGF1 Conjugate Based on AlphaFold for Type 2 Diabetes Mellitus

Drugs for metabolic diseases usually require systemic administration and act on multiple tissues, which may produce some unpredictable side effects. There have been many successful studies on targeted drugs, especially antitumor drugs. However, there is still little research on metabolic disease drugs targeting specific tissues. Fibroblast growth factor 1 (FGF1) is a potential therapy for type 2 diabetes (T2D) without the risk of hypoglycemia. However, the major impediment to the clinical application of FGF1 is its mitogenic potential. We previously engineered an FGF1 variant (named FGF1^ΔHBS) to tune down its mitogenic activity via reducing the heparin-binding ability. However, other notable side effects still remained, including severe appetite inhibition, pathogenic loss of body weight, and increase in fatality rate. In this study, we used AlphaFold2 and PyMOL visualization tools to construct a novel FGF1^ΔHBS conjugate fused with skeletal muscle-targeted (MT) peptide through a flexible peptide linker termed MT-FGF1^ΔHBS. We found that MT-FGF1^ΔHBS specifically homed to skeletal muscle tissue after systemic administration and induced a potent glucose-lowering effect in T2D mice without hypoglycemia. Mechanistically, MT-FGF1^ΔHBS elicits the glucose-lowering effect via AMPK activation to promote the GLUT4 expression and translocation in skeletal muscle cells. Notably, compared with native FGF1^ΔHBS, MT-FGF1^ΔHBS had minimal effects on food intake and body weight and did not induce any hyperplasia in major tissues of both T2D and normal mice, indicating that this muscle-homing protein may be a promising candidate for T2D treatment. Our targeted peptide strategy based on computer-aided structure prediction in this study could be effectively applied for delivering agents to functional tissues to treat metabolic or other diseases, offering enhanced efficacy and reducing systemic off-target side effects.