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

Abstract

BACKGROUND:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Javier P Martinez, Bettina Hinkelmann, Eric Fleta-Soriano, Heinrich Steinmetz, Rolf Jansen, Juana Diez, Ronald Frank, Florenz Sasse, Andreas Meyerhans
• Journal: Microbial cell factories (Microb Cell Fact) Vol. 12 Pg. 85 (Sep 24 2013) ISSN: 1475-2859 [Electronic] England
• PMID: 24063434 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents

Topics

• Anti-HIV Agents (isolation & purification, pharmacology)
• Drug Resistance
• High-Throughput Screening Assays (methods)
• Humans
• Myxococcales (chemistry)