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

Microbial Cell Factories

Research

Bettina Hinkelmann¹  Florenz Sasse¹  Ronald Frank¹  Eric Fleta-Soriano²  Javier P Martinez²  Andreas Meyerhans³  Juana Diez⁴  Heinrich Steinmetz⁵  Rolf Jansen⁵ 

[1] Department of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany;Department of Experimental and Health Sciences, Infection Biology Group, Universitat Pompeu Fabra, Barcelona, Spain;Department of Experimental and Health Sciences, Infection Biology Group, Universitat Pompeu Fabra, Barcelona, Spain;Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain;Department of Experimental and Health Sciences, Molecular Virology Group, Universitat Pompeu Fabra, Barcelona, Spain;Department of Microbial Drugs, Helmholtz Centre for Infection Research, Braunschweig, Germany;

关键词: Human Immunodeficiency Virus;    Human Immunodeficiency Virus Infection;    Selectivity Index;    Enfuvirtide;    Epothilon;   

DOI  :  10.1186/1475-2859-12-85

 received in 2013-08-06, accepted in 2013-09-19,  发布年份 2013

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Martinez et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.