International Symposium on Molecular Medicine edition:17 location:Athens, Greece date:9-11 October 2014
The human immunodeficiency virus (HIV) needs the CD4 cell surface glycoprotein for the entry and infection of host cells such as T-helper lymphocytes. Efficient infection requires a high cellular expression level of the primary receptor CD4, together with the chemokine co-receptors CCR5 and/or CXCR4. Thus, if HIV access to CD4 can be prevented, an essential early step in viral entry is inhibited. We have previously reported a class of small synthetic HIV entry inhibitor compounds called cyclotriaza-disulfonamides (CADA). These compounds cause reversible down-modulation of surface CD4 receptor expression, explaining their anti-HIV activity. Here, we describe how structural variation of several CADA analogs affects the ability to lower surface CD4 expression and how this correlates with their anti-HIV potency. Seventeen CADA compounds were synthesized to investigate variations in the sulfonamide sidechain, head group substituents or ring size. The CD4 down-modulating activity of the compounds was tested on a MT-4 T-cell line and on a CHO cell line expressing a CD4-YFP reporter protein, resulting in IC50 values ranging between 140 nM and 26 µM for MT-4 cells and 60 nM to 18 µM for CHO cells. The analogs were also tested against HIV NL4.3 (X4) infection of MT-4 cells. In accordance with previous work, the anti-HIV data of these new CADA analogs correlated well with their level of CD4 down-modulation, confirming the link between CD4 expression levels and the efficiency of HIV infection. From structure-activity data, we conclude that high electron density in one of the sulfonamide chains is generally beneficial for compound activity. Also, the higher activity of unsymmetrical CADA analogs suggested a two-site binding model for the CADA compounds. Remarkably, analogs with a smaller 11-ring backbone showed only slight reduction in compound potency as compared to their 12-ring counterparts. As size variations in the essential cyclic backbone are now proven to be a feasible path of structural exploration, future synthesis will be focused on optimization of not only the sulfonamide side chains and the head group, but also of the ring size.