Multiple binding modes for the receptor-bound conformations of cyclic AII agonists

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Molecular Pharmacology

Background:

• Angiotensin II (AII) is a key peptide hormone regulating blood pressure.
• AII binds to its receptor, with a proposed turn at residue four.
• Understanding AII-receptor interactions is crucial for cardiovascular drug development.

Purpose of the Study:

• To investigate the role of specific amino acid residues in AII's receptor binding.
• To explore how molecular constraints influence AII's affinity and activity.
• To gain insights into the conformational dynamics of AII during receptor binding.

Main Methods:

• Synthesis of AII analogs with disulfide bridges between residues 3 and 5.
• Incorporation of 4-mercaptoproline into AII analogs.
• Conformational analysis of novel bicyclic AII systems.
• Assessment of receptor binding affinity for synthesized analogs.

Main Results:

• AII analogs with disulfide bridges between residues 3 and 5 retained significant activity.
• Incorporation of 4-mercaptoproline into constrained bicyclic systems maintained high receptor affinity.
• Unexpectedly, an antiparallel dimer of [Sar1,Cys3,5]-AII with an extended backbone also showed activity.

Conclusions:

• Constrained bicyclic AII analogs provide detailed insights into molecular recognition of AII residues 3-5.
• The unexpected activity of the extended dimer suggests AII agonists may adopt diverse backbone conformations upon receptor binding.
• These findings advance the understanding of Angiotensin II receptor interactions and potential therapeutic strategies.