[Cyclotriazadisulfonamides as new and unique HIV entry inhibitors].

Abstract

In order to infect a target cell, the HIV envelope glycoprotein gp120 has to interact with the CD4 receptor, which serves as the primary virus receptor. For most HIV strains, the successful infection of their target cells is mainly dependent on the expression of the CD4 surface molecule which can be considered as an ideal target with multiple windows of opportunity for therapeutic intervention. Therefore, drugs that interfere with the CD4 receptor, and thus inhibit viral entry, may be promising agents for the treatment of AIDS. Here we describe the discovery and characterization of the CD4-targeted HIV entry inhibitors cyclotriazadisulfonamides. They repesent a novel class of small molecule antiviral agents with an unique mode of action. The lead compound, CADA, specifically interferes with cellular CD4 receptor expression and is active against a wide variety of HIV strains at submicromolar levels when evaluated in different cell-types such as T cells, monocytes and dendritic cells. Moreover, a strict correlation has been demonstrated between anti-HIV activity and CD4 down-modulation of about 20 different CADA analogs. In addition, CADA acted synergistically in combination with other FDA-approved anti-HIV drugs. The broad spectrum antiviral activity of CADA against several different subtypes of HIV supports the possible application of this compound as a microbicide. Finally, the development of fluorescent CADA analogs made it feasible to study receptor and its down-modulator simultaneously. These CADA-compounds with reversible CD4 down-modulating potency will be valuable tools in further studies on receptor modulation, and in deciphering the process that plays a role during the complicated interactions between HIV-gp120 and the cellular membrane, which ultimately will lead to a more efficient treatment of HIV-infections.