Isolation and Structure of Antagonists of Chemokine Receptor (CCR5)

Abstract

Human CCR5 is a G-coupled receptor that binds to the envelope protein gp120 and CD4 and mediates the HIV-1 viral entry into the cells. The blockade of this binding by a small molecule receptor antagonist could lead to a new mode of action agent for HIV-1 and AIDS. Screening of natural product extracts led to the identification of anibamine (1), a novel pyridine quaternary alkaloid as a TFA salt, from Aniba sp.; ophiobolin C from fermentation extracts of fungi Mollisia sp.; and 19,20-epoxycytochalasin Q from Xylaria sp. Formation of the TFA salt of anibamine is plausibly an artifact of the isolation. The identity of the natural counterion is unknown. Anibamine.TFA competed for the binding of 125I-gp120 to human CCR5 with an IC50 of 1 microM. Ophiobolin C and 19,20-epoxycytochalasin Q exhibited binding IC50) values of 40 and 60 microM, respectively.

A Novel Aspochalasin with HIV-1 Integrase Inhibitory Activity from Aspergillus flavipes

“…For example Flashner et al demonstrated that the conjugated a,b-keto unsaturated group in the macrolide moiety of cytochalasin A was important for conveying antibacterial activity against Gram-positive bacteria [16]. More recently aspochalasins IϳK were found to exhibit moderate cytotoxicity against several NCI cell lines and in a separate publication 19,20-epoxycytochalsin Q was noted to be an inhibitor of CCR5 which is implicated in HIV infection [17]. Whilst the cytochalasins identified in this study are able to inhibit the activity of integrase in in vitro enzyme assays, in their current forms they are not able to inhibit the replication of HIV-1.…”

Optimization of submerged culture conditions for mycelial biomass production with enhanced antibacterial activity of the medicinal macro fungus Xylaria sp. Strain R006 against drug resistant bacterial pathogens

“…Although they are found mostly on wood, some species are found on sawdust, leaf and dung or soil. The genus Xylaria has been proven to be a valuable source of bioactive agents such as chemokine receptor (CCR5) antagonist 19, 20-epoxycytochalasin Q (Jayasuriya et al 2004), the antifungal multiplolides A and B (Boonphong et al 2001), the NPY Y5 receptor antagonists xylarenals A and B (Smith et al 2002) and the cytotoxic eremophilanolides (Isaka et al 2010). Recently, we have isolated bioactive metabolites producing Xylaria spp.…”

Terpenoid and Phenolic Metabolites from the Fungus Xylaria sp. Associated with Termite Nests

“…Previous investigations have revealed that fungi of the genus Xylaria are a rich source of structurally diverse natural products. Examples include the HIV-1 integrase inhibitor integric acid [1], the cytotoxic agents xyloallenolide A [2] and eremophilanolides [3], the antifungal metabolites multiplolides A and B [4], the acetylcholinesterase inhibitors xyloketals [5], the NPY Y5 receptor antagonists xylarenals A and B [6], the chemokine receptor antagonist 19,20-epoxycytochalasin Q [7], the anti-herpes simplex virus agent mellisol [8].…”