Unsymmetrical cyclotriazadisulfonamide (CADA) compounds as human CD4 receptor down-modulating agents
Violeta G Demillo1, Florian Goulinet-Mateo, Jessica Kim
1Department of Chemistry, University of Nevada, Reno, Nevada 89557-0216, USA.
Journal of Medicinal Chemistry
|August 2, 2011
Summary
New Cyclotriazadisulfonamide (CADA) compounds effectively inhibit HIV by down-modulating CD4. The most potent compound, VGD020, shows significant activity, supporting a zipper-type binding mechanism.
Area of Science:
- Medicinal Chemistry
- Virology
- Molecular Biology
Background:
- Cyclotriazadisulfonamide (CADA) compounds inhibit HIV by down-modulating CD4.
- The precise molecular target and binding mode of CADA remain unelucidated.
- Previous research suggested an unsymmetrical binding model for CADA.
Purpose of the Study:
- To synthesize and evaluate novel, unsymmetrical CADA compounds.
- To test the proposed unsymmetrical binding model for CADA.
- To identify potent CADA analogs for HIV inhibition.
Main Methods:
- Development of synthetic routes for diverse, unsymmetrical CADA derivatives.
- Synthesis of 13 novel unsymmetrical CADA compounds and one symmetrical analog.
- Assessment of CD4 down-modulation potency in CHO·CD4-YFP cells.
Main Results:
- A range of potencies for CD4 down-modulation was observed among the synthesized compounds.
- VGD020 emerged as the most potent CADA compound, with an IC(50) of 46 nM.
- VGD029 was identified as the most potent fluorescent analog (IC(50) = 730 nM).
- Structure-activity relationship analysis supported a zipper-type binding mechanism.
Conclusions:
- The synthesized CADA compounds demonstrate varying efficacy in CD4 down-modulation.
- The findings are consistent with a zipper-type binding mechanism, reducing entropic costs.
- This study provides valuable insights into CADA structure-activity relationships for HIV inhibition.
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