Multivalent drug design and inhibition of cholera toxin by specific and transient protein-ligand interactions.
Multivalent inhibitors of the cholera toxin B pentamer are potential therapeutic drugs for treating cholera and serve as models for demonstrating multivalent ligand effects through a structure-based approach. A crucial yet often overlooked aspect of multivalent drug design is the length, rigidity and chemical composition of the linker used to connect multiple binding moieties. To specifically study the role of chemical linkers in multivalent ligand design, we have synthesized a series of compounds with one and two binding motifs connected by several different linkers. These compounds have affinity for and potency against the cholera toxin B pentamer despite the fact that none can simultaneously bind two toxin receptor sites. Results from saturation transfer difference NMR reveal transient, non-specific interactions between the cholera toxin and linker groups contribute significantly to overall binding affinity of monovalent compounds. However, the same random protein-ligand interactions do not appear to affect binding of bivalent molecules. Moreover, the binding affinities and potencies of these 'non-spanning' bivalent ligands appear to be wholly independent of linker length. Our detailed analysis identifies multiple effects that account for the improved inhibitory potencies of bivalent ligands and suggest approaches to further improve the activity of this class of compounds.
Liu
Jiyun
J
Department of Chemistry, University of Washington, Seattle, WA 98195, USABiomolecular Structure Center, University of Washington, Seattle, WA 98195, USADepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Begley
Darren
D
Department of Chemistry, University of Washington, Seattle, WA 98195, USABiomolecular Structure Center, University of Washington, Seattle, WA 98195, USADepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Mitchell
Daniel D
DD
Department of Chemistry, University of Washington, Seattle, WA 98195, USABiomolecular Structure Center, University of Washington, Seattle, WA 98195, USADepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Verlinde
Christophe L M J
CLMJ
Department of Chemistry, University of Washington, Seattle, WA 98195, USABiomolecular Structure Center, University of Washington, Seattle, WA 98195, USADepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Varani
Gabriele
G
Department of Chemistry, University of Washington, Seattle, WA 98195, USABiomolecular Structure Center, University of Washington, Seattle, WA 98195, USADepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Fan
Erkang
E
Department of Chemistry, University of Washington, Seattle, WA 98195, USABiomolecular Structure Center, University of Washington, Seattle, WA 98195, USADepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA.
D002771:Cholera / Q000188:drug therapy; D002772:Cholera Toxin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry; D015195:Drug Design; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D011485:Protein Binding; D013329:Structure-Activity Relationship
D003432:Cross-Linking Reagents; D008024:Ligands; D002772:Cholera Toxin