Adipotide (Prohibitin-TP01)

Overview

Chimeric adipose-vasculature-targeted peptidomimetic targeting prohibitin/annexin A2 on white adipose tissue endothelium, delivering pro-apoptotic D-(KLAKLAK)2 motif. In obese primates it produced rapid fat loss with improved insulin resistance, yet development halted after Phase 1 due to kidney safety signals.

CKGGRAKDC ligand homes to prohibitin/annexin A2 on white-fat endothelium; linked D-(KLAKLAK)2 disrupts mitochondrial membranes post-internalization, triggering localized endothelial apoptosis and adipocyte loss.

Selective white adipose tissue vascular targeting produced 7-15% body-weight loss over 4 weeks in obese macaques.

Improved insulin response (reduced insulin AUC) following fat-mass reduction in primates.

Weight loss without primary appetite suppression; peripheral vascular approach.

Mechanism

Adipotide targets adipose tissue vascular endothelium directly, causing localized endothelial apoptosis and adipocyte loss via a peripheral vascular mechanism. Semaglutide suppresses appetite centrally via GLP-1 receptors. Adipotide achieves weight loss without appetite suppression, making it mechanistically distinct from appetite suppressants.

Research areas

• Chimeric adipose-vasculature-targeted peptidomimetic targeting prohibitin/annexin A2 on white adipose tissue endothelium, delivering pro-apoptotic D-(KLAKLAK)2 motif. In obese primates it produced rapid fat loss with improved insulin resistance, yet development halted after Phase 1 due to kidney safety signals.
• CKGGRAKDC ligand homes to prohibitin/annexin A2 on white-fat endothelium; linked D-(KLAKLAK)2 disrupts mitochondrial membranes post-internalization, triggering localized endothelial apoptosis and adipocyte loss.
• Selective white adipose tissue vascular targeting produced 7-15% body-weight loss over 4 weeks in obese macaques.
• Improved insulin response (reduced insulin AUC) following fat-mass reduction in primates.
• Weight loss without primary appetite suppression; peripheral vascular approach.

Research notes

• Mild creatinine elevation
• Electrolyte shifts
• Dose-dependent proximal tubule changes (reversible in primates)
• Sustained creatinine elevation or oliguria
• Progressive electrolyte abnormalities
• Severe injection-site reactions or systemic symptoms
• Unexpected toxicity
• Pregnancy/lactation (not studied)
• Dehydration
• Concurrent nephrotoxic medications

Reported effects in literature

• Phase 1 trials showed dose-dependent mild creatinine elevation and reversible proximal tubule changes in kidney tissue. Although these effects reversed in primates, the kidney safety signals were considered significant enough to halt further clinical development. This remains a major concern for any consideration of Adipotide use.

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