Supramolecular optical chemosensors are abiotic molecular devices that bind analytes by noncovalent interactions, producing a change in light absorption or fluorescence. This review summarizes recent progress in the development of such chemosensors for organic analytes based on artificial receptors. Important design considerations, such as analyte affinity, choice of chromophore or fluorophore, binding selectivity, and optical signaling mechanism are briefly discussed. Chemists have fashioned chemosensors from a wide range of molecular structures, including polyalcohols, crown ethers, calixarenes, helicenes, sterically geared tripods, metal complexes, pinwheels, porphyrins, and fused-ring heterocycles. Analytes of interest include amines, carboxylic acids, amino acids, hydroquinones, alkaloids, carbohydrates, peptides, urea and creatinine.
A small chemical drug CADA specifically binds to the signal peptide of the membrane pre-protein CD4, disturbing its synthesis, impeding the routing to and expression on the cell surface.
The novel antiviral agent cyclotriazadisulfonamide (CADA) inhibited human immunodeficiency virus (HIV) (IC50, 0.3-3.2 microM) and human herpesvirus 7 (HHV-7) infection (IC50, 0.3-1.5 microM) in T-cell lines and PBMCs. When T-cells were pretreated with CADA for 24 h, they became markedly protected from viral infection. Flow cytometric analysis revealed a significant decrease in the expression of the CD4 glycoprotein, the primary receptor needed for entry of both viruses. Moreover, the antiviral activity of CADA correlated with its ability to down-modulate the CD4 receptor. CADA did not alter the expression of any other cellular receptor (or HIV coreceptor) examined. Time course experiments showed that CD4 down-modulation by CADA differs in mechanism from the effects of aurintricarboxylic acid, which binds directly to CD4, and phorbol myristate acetate, which activates protein kinase C. Further analysis of CD4 mRNA levels suggested that CADA was not involved in the regulation of CD4 expression at a transcriptional level, but very likely at (post) translational levels. This unique mechanism of action makes CADA an important lead in developing new drugs for treatment of AIDS, autoimmune diseases, and inflammatory disorders.
Compounds that can specifically downmodulate the CD4 receptor in PBMC have broad-spectrum anti-HIV activity against primary isolates and act synergistically when used in conjunction with currently available antiretroviral drugs. They deserve further study as potential candidate anti-HIV drugs.
HIV attachment via the CD4 receptor is an important target for developing novel approaches to HIV chemotherapy. Cyclotriazadisulfonamide (CADA) inhibits HIV at submicromolar levels by specifically downmodulating cell-surface and intracellular CD4. An effective five-step synthesis of CADA in 30% overall yield is reported. This synthesis has also been modified to produce more than 50 analogues. Many tailgroup analogues have been made by removing the benzyl tail of CADA and replacing it with various alkyl, acyl, alkoxycarbonyl and aminocarbonyl substituents. A series of sidearm analogues, including two unsymmetrical compounds, have also been prepared by modifying the CADA synthesis, replacing the toluenesulfonyl sidearms with other sulfonyl groups. Testing 30 of these compounds in MT-4 cells shows a wide range of CD4 down-modulation potency, which correlates with ability to inhibit HIV-1. Threedimensional quantitative structure-activity relationship (3D-QSAR) models were constructed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The X-ray crystal structures of four compounds, including CADA, show the same major conformation of the central 12-membered ring. The solid-state structure of CADA was energy minimized and used to generate the remaining 29 structures, which were similarly minimized and aligned to produce the 3D-QSAR models. Both models indicate that steric bulk of the tail group, and, to a lesser extent, the sidearms mainly determine CD4 down-modulation potency in this series of compounds.
An artificial receptor has been designed to bind creatinine with a color change (chromogenic response) caused by proton transfer from one end of the receptor to the other. The receptor was synthesized and found to extract creatinine from water into chlorocarbon solvents. The color change in the organic layer is specific for creatinine relative to other organic solutes, and it is selective for creatinine relative to sodium, potassium, and ammonium ions. The chromogenic mechanism is revealed by x-ray crystal structures of creatinine, the free receptor, and the complex, showing "induced fit" binding resulting from electronic complementarity between host and guest.
9-Benzyl-3-methylene-1,5-di-p-toluenesulfonyl-1,5,9-triazacyclododecane (CADA) has been identified as a novel antiviral lead compound with significant anti-human immunodeficiency virus and anti-human herpesvirus 7 activity. Surprisingly, this compound selectively decreased the expression of the CD4 glycoprotein, the primary receptor needed for the entry of both viruses. Herein, we describe the CD4 down-modulating and antiviral potencies of more than 25 CADA derivatives. Flow cytometric evaluation of cellular CD4 receptor expression in T cells demonstrated the specific CD4 down-modulating capacity of the CADA derivatives, with IC 50 values similar to those obtained in the antiviral assays. The close correlation observed between the CD4 down-regulating and anti-HIV potencies of the CADA derivatives further points to CD4 receptor downmodulation as the primary mode of antiviral action for this group of compounds.It is well known that infection of target cells by human immunodeficiency virus (HIV) is dependent on the presence of the CD4 surface molecule, which serves as the main virus receptor (Dalgleish et al., 1984;Klatzmann et al., 1984). Also, human herpesvirus 7 (HHV-7) uses the CD4 receptor for viral entry (Furukawa et al., 1994;Lusso et al., 1994). Although CD4 is the primary receptor for HIV entry, several CD4-independent HIV-1 strains have been reported (Dumonceaux et al., 1998;Hoffman et al., 1999;Kolchinsky et al., 1999;LaBranche et al., 1999). These viruses, derived by passage on CD4-negative, CCR5-positive, or CXCR4-positive cells, can infect their target cells in the absence of the CD4 receptor by using a chemokine receptor. Interestingly, CD4-independent HIV isolates can be obtained from HIV-infected persons but these viruses show an enhanced sensitivity to antibody mediated neutralization Edwards et al., 2001;Kolchinsky et al., 2001).CD4 is a type I integral membrane glycoprotein that is expressed mainly on the surface of thymocytes, T helper lymphocytes, and cells of the macrophage/monocyte lineage (Maddon et al., 1986). It participates in the maturation of T lymphocytes and, as an intercellular adhesion molecule, plays an important role in the stabilization of the interaction between T cell receptors on T cells and MHC II complexes on antigen-presenting cells. After the antigenic stimulation of T lymphocytes, CD4 also provides a physical noncovalent link to p56 lck protein tyrosine kinase, resulting in cell proliferation and interleukin-2 production (reviewed by Weiss and Littman, 1994).The expression of the CD4 receptor is tightly regulated in various physiological processes. During the development of T cells in the thymus, the CD4 Ϫ CD8 Ϫ double-negative cells become CD4 ϩ CD8 ϩ double-positive before they differentiate into single positive T cells (Zuniga-Pflucker et al., 1989). Also, after antigen-induced T cell activation, CD4 is quickly internalized via clathrin-coated pits, leading to a temporary desensitization of the cell (Pelchen-Matthews et al., 1992). In nonlymphoid cells, CD4 i...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.