Compound Overview
Semaglutide is a GLP-1 receptor agonist developed through structural modification of native GLP-1. The compound incorporates a C18 fatty diacid chain attached via a linker to lysine at position 34, enabling albumin binding and extending the half-life to approximately 165–184 hours — sufficient for once-weekly administration in research protocols.
Structural Characteristics
The semaglutide molecule shares 94% sequence homology with native human GLP-1. Key structural modifications include:
- —Aib substitution at position 8: Prevents DPP-4 enzymatic cleavage
- —Lysine to arginine substitution at position 34: Provides attachment point for fatty acid chain
- —C18 fatty diacid: Enables reversible albumin binding for extended half-life
Pharmacokinetic Profile
165–184h
Half-life enabling once-weekly dosing in research protocols
Following subcutaneous administration, semaglutide reaches peak plasma concentration (Tmax) at 1–3 days. Bioavailability is approximately 89% following subcutaneous injection. The compound is primarily eliminated through metabolic pathways with minor renal excretion.
STEP Research Program Outcomes
The Semaglutide Treatment Effect in People with obesity (STEP) program comprised 8 trials examining semaglutide 2.4mg in over 4,500 research participants.
14.9%
STEP 1 trial mean weight reduction vs 2.4% placebo over 68 weeks (n=1,961)
Key findings across the STEP program:
- —STEP 1: 14.9% weight reduction over 68 weeks
- —STEP 3: 16.0% weight reduction with lifestyle intervention
- —STEP 4: Weight regain upon discontinuation confirmed ongoing administration requirement
- —STEP 5: 15.2% weight reduction maintained at 104 weeks
Receptor Binding and Selectivity
Semaglutide demonstrates high selectivity for the GLP-1 receptor with minimal off-target activity. Receptor binding studies demonstrate Ki values in the low nanomolar range, with greater than 1,000-fold selectivity over glucagon and GIP receptors.