Sch 213766, A Novel Chemokine Receptor CCR-5 Inhibitor from Chaetomium globosum

A novel fungal secondary metabolite, Sch 213766 was isolated from the fungal fermentation broth of Chaetomium globosum as the chemokine receptor CCR-5 inhibitor and shown to be the methyl ester of the previously described tetramic acid Sch 210972 on the basis of UV, MS and NMR spectral data analyses. Sch213766 exhibited an IC 50 value of 8.6 mM in the CCR-5 receptor in vitro binding assay. individuals called highly active antiretroviral therapy or HAART consists of three approved antiretroviral drugs, typically two reverse transcriptase inhibitors and one protease inhibitor to suppress HIV infection and reduce morbidity and mortality. Although HAART has proven effective to reduce viral load in patients with continuous dosing for over three years, this drug combination approach has not yet illustrated the capability of complete viral elimination from an infected individual. In addition, long- term toxicity and adverse drug-drug interactions of commercially available anti-HIV drugs are major concerns in medical treatments (2). Furthermore, the emergence of viral resistance to protease and reverse transcriptase inhibitors has been reported due to the increasing use of antiretroviral agents (3). Therefore, searching for effective anti HIV-1 infection agents with new mechanisms of action has become an urgent need. Recent studies indicated that binding to specific, cell surface co-receptors is an essential process before HIV-1 enters the targeted cells of the immune system. The chemokine receptor CCR-5 on macrophages, monocytes and T-cells, which belongs to the super family of seven-trans-membrane G-protein coupled receptors (GPCRs), has been identified as the surface co-receptor with the CD 4 molecule for viral entry (4). The endogenous ligands of the CCR-5 receptor are the