Design and cellular kinetics of dansyl-labeled CADA derivatives with anti-HIV and CD4 receptor down-modulating activity

Simultaneous inhibition of human CD4 and 4-1BB biogenesis suppresses cytotoxic T lymphocyte proliferation

“…This direct down-modulatory effect of CADA on 4-1BB was almost complete and similar to its effect on hCD4 (IC50 of 0.24 µM and 0.30 μM, respectively), demonstrating that 4-B11 is a valuable substrate of CADA ( Figure 9B). The down-modulating effect of CADA on 4-1BB is reversible in nature, as evidenced by the reexpression of 4-1BB after wash-out of CADA ( Figure 9C), an effect that is observed for hCD4 as well (Figure 9-figure supplement 1) as reported earlier (Vermeire et al, 2014;Vermeire et al, 2007). As summarized in Figure 9D, in addition to the potent inhibition of hCD4 and 4-1BB expression, CADA also partially reduced cellular levels of other co-stimulatory receptors in transfected cells.…”

“…The antiviral effect of this synthetic macrocycle is due to down-modulation of the CD4 protein, the primary entry receptor for HIV (Vermeire et al, 2003). This down-modulating activity of CADA is reversible in vitro: when treatment is ceased, cellular CD4 expression is rapidly restored to normal levels (Vermeire et al, 2007). Additionally, CADA does not compromise cellular viability as was demonstrated by long-term (about 1 year) exposure of a T cell line to CADA, with full recovery of CD4 expression when treatment was terminated (Vermeire et al, 2014).…”

Small Molecule Cyclotriazadisulfonamide Abrogates the Upregulation of the Human Receptors CD4 and 4-1BB and Suppresses In Vitro Activation and Proliferation of T Lymphocytes

“…The antiviral effect of this synthetic macrocycle is due to down-modulation of the CD4 protein, the primary entry receptor for HIV (20). This down-modulating activity of CADA is reversible in vitro: when treatment is ceased, cellular CD4 expression is rapidly restored to normal levels (21). Additionally, CADA does not compromise cellular viability as was demonstrated by long-term (about 1 year) exposure of a T cell line to CADA, with full recovery of CD4 expression when treatment was terminated (22).…”

The signal peptide as a new target for drug design

“…48 The macrocyclic triamine cyclotriazadisulfonamide (CADA) is a small molecule that inhibits replication of various strains of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) by selectively down-modulating expression of cell-surface cluster of differentiation 4 (CD4). 27,46,[64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79] This type 1 integral transmembrane glycoprotein is expressed on immune cells and is the primary receptor required by HIV to enter host cells. CADA compounds are radically different from conventional anti-HIV agents that have viral targets and are highly susceptible to onset of resistance by mutation and selection mechanisms.…”