Identification of myxobacteria-derived HIV inhibitors by a high-throughput two-step infectivity assay

Abstract

BackgroundDrug-resistance and therapy failure due to drug-drug interactions are the main challenges in current treatment against Human Immunodeficiency Virus (HIV) infection. As such, there is a continuous need for the development of new and more potent anti-HIV drugs. Here we established a high-throughput screen based on the highly permissive TZM-bl cell line to identify novel HIV inhibitors. The assay allows discriminating compounds acting on early and/or late steps of the HIV replication cycle.ResultsThe platform was used to screen a unique library of secondary metabolites derived from myxobacteria. Several hits with good anti-HIV profiles were identified. Five of the initial hits were tested for their antiviral potency. Four myxobacterial compounds, sulfangolid C, soraphen F, epothilon D and spirangien B, showed EC50 values in the nM range with SI > 15. Interestingly, we found a high amount of overlapping hits compared with a previous screen for Hepatitis C Virus (HCV) using the same library.ConclusionThe unique structures and mode-of-actions of these natural compounds make myxobacteria an attractive source of chemicals for the development of broad-spectrum antivirals. Further biological and structural studies of our initial hits might help recognize smaller drug-like derivatives that in turn could be synthesized and further optimized.

Modification of the Host Cell Lipid Metabolism Induced by Hypolipidemic Drugs Targeting the Acetyl Coenzyme A Carboxylase Impairs West Nile Virus Replication

“…Indeed, the clinical value of lipid-lowering agents such as the statins, which are cholesterol synthesis inhibitors broadly used against cardiovascular diseases, supports the feasibility of therapeutic interventions targeting the lipid metabolism (42). Consistently, hypolipidemic drugs targeting the ACC are being evaluated for the treatment of multiple human disorders from certain cancers to obesity and diabetes (20,21) and even viral infections (18,34,43). In addition, the results obtained with hypolipidemic agents (i.e., nordihydroguaiaretic acid) that target cellular factors other than ACC also support the feasibility of lipid-based antiviral approaches (17,44).…”

Identification of a dibenzocyclooctadiene lignan as a HIV-1 non-nucleoside reverse transcriptase inhibitor

“…27 As shown in Figure 1(e) and (f), HDS2 exerted antiviral activity against both X4 and R5-tropic viruses in this assay, with similar EC 50 s being obtained as in the MT-4/MTT assay ( Table 1), showing that HDS2 targets an early step in HIV-1 replication (between entry and integration).…”

Antiviral drug discovery: broad-spectrum drugs from nature

“…Indeed, good examples are the cyclophilin inhibitors as mentioned above. More recent examples are the described overlapping hits from a myxobacterial library that inhibit both HIV and HCV as well as host factors involved in the processing machinery of cellular and viral RNA 55,237,238,263 .…”

“…Here structures (17), (18), (19), (20) and (21) Both antiviral screens also identified two highly specific V-ATPase inhibitors, apicularen (22) and archazolid (23), as anti-HIV and anti-HCV hits 237,238 . Recently, Müller et al also described apicularen as an inhibitor of HPV replication 236 .…”