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

Martinez, Javier P.; Hinkelmann, Bettina; Fleta Soriano, Eric, 1983-; Steinmetz, Heinrich; Jansen, Rolf; Díez Antón, Juana, 1962-; Frank, Ronald; Sasse, Florenz; Meyerhans, Andreas

doi:http://dx.doi.org/10.1186/1475-2859-12-85

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

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Citació

Martinez JP, Hinkelmann B, Fleta-Soriano E, Steinmetz H, Jansen R, Diez J et al. Identification of myxobacteria-derived HIV inhibitors by a high-throughput two-step infectivity assay. Microb. Cell Fact. 2013;12(1):85. DOI: 10.1186/1475-2859-12-85

Resum

Drug-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. The 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. The 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.