Cyclotriazadisulfonamide (CADA) compounds are macrocycles that down-modulate human CD4 by selectively inhibiting co-translational translocation of the nascent protein across the ER membrane, thus acting as HIV entry inhibitors. This ability is also of interest for developing potential immunomodulatory drugs. CADA is the first small molecule known to selectively down-modulate any protein by targeting its signal sequence during translation of the nascent protein.  We have synthesized potent CADA analogs (IC<sub>50 </sub>&lt; 0.1 μM) having electron donating groups on one of the arenesulfonamide side arms and found that CD4 down-modulating potencies correlate with the electric dipole moment of this side arm. This suggests that one arm makes an attractive interaction with one or more critical amino acid residues of the signal sequence. Our mechanistic hypothesis is that the small molecule stabilizes a folded conformation of the nascent protein within the transmembrane channel, blocking CD4 translocation into the ER lumen. Current advances on modifying properties of CADA compounds and on identifying molecular details of the mechanism of action are described.

Synthetic and mechanistic studies of cyclotriazadisulfonamide (CADA) down-modulators of human CD4

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.