Title: Anti-HIV activity and CD4 receptor down-modulating effect of cyclotriazadisulfonamide (CADA) structural analogs
Authors: Van Puyenbroeck, Victor
Bell, Thomas W
Schols, Dominique
Chawla, Reena
Ali, Rameez
Scarbrough, Emily D
Vermeire, Kurt
Issue Date: 12-Oct-2014
Conference: Antivirals Congress edition:3 location:Amsterdam, The Netherlands date:12-14 October 2014
Abstract: The human immunodeficiency virus (HIV) requires 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 cyclotriazadisulfonamides (CADA). These compounds cause reversible down-modulation of surface CD4 receptor expression, explaining their anti-HIV activity. Here, we describe how that 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 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.
Publication status: published
KU Leuven publication type: IMa
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)

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