CT-388: Molecular Structure

Molecular Structure and Properties#

CT-388 is a unimolecular peptide-based dual GLP-1R/GIPR agonist developed by Carmot Therapeutics (now part of Roche/Genentech). The exact amino acid sequence and detailed molecular structure have not been publicly disclosed. CT-388 is described as a cAMP signal-biased agonist at both GLP-1 and GIP receptors with minimal to no beta-arrestin recruitment.

Biased Signaling Mechanism#

The defining molecular feature of CT-388 is its biased signaling profile:

• cAMP signaling: Full agonist activity at both GLP-1R and GIPR through G-protein coupled cAMP pathway
• Beta-arrestin: Minimal to no beta-arrestin recruitment at either receptor
• Receptor internalization: Significantly reduced compared to balanced agonists
• Receptor desensitization: Minimized due to reduced internalization

This biased signaling profile distinguishes CT-388 from tirzepatide and other dual GLP-1/GIP agonists that activate both G-protein and beta-arrestin pathways.

Implications of Biased Signaling#

Known Molecular Properties#

Pharmacokinetics#

Detailed pharmacokinetic data for CT-388 have not been fully published. Key observations:

• Half-life: Supports once-weekly subcutaneous dosing, indicating a terminal half-life of several days
• Dose proportionality: Multiple dose levels evaluated in Phase 2 (up to 24 mg) showed dose-dependent weight loss
• No plateau: Progressive weight loss at 48 weeks suggests sustained receptor engagement throughout the dosing interval
• Subcutaneous bioavailability: Sufficient for once-weekly dosing to produce 22.5% weight loss

Comparison with Tirzepatide#

Both CT-388 and tirzepatide are dual GLP-1/GIP agonists, but they differ fundamentally in signaling:

Receptor Pharmacology#

CT-388 was specifically engineered for biased signaling:

• GLP-1 receptor: Potent cAMP agonism with minimal beta-arrestin recruitment, reducing GLP-1R internalization
• GIP receptor: Potent cAMP agonism with minimal beta-arrestin recruitment, reducing GIPR internalization

The reduced receptor internalization theoretically maintains higher receptor density on the cell surface, allowing for more sustained signaling per dose. This may contribute to the high efficacy observed in clinical trials (22.5% weight loss at 48 weeks).

Preclinical Molecular Data#

The Cell Metabolism publication (PMID 41319798) characterized CT-388 as a unimolecular peptide-based dual GLP-1R/GIPR agonist. Preclinical studies demonstrated:

• Improved glycemic control in mice and monkeys
• Body weight reduction and appetite suppression in mice
• Improved MASH pathology in mouse models
• Confirmation of the biased signaling profile in vitro

Related Reading#

• CT-388 overview and research guide
• Peptides similar to CT-388
• CT-388 research evidence