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


CONCLUSIONS
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.
Infection Biology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain. andreas.meyerhans@upf.edu.
Javier P
JP
Martinez
Bettina
B
Hinkelmann
Eric
E
Fleta-Soriano
Heinrich
H
Steinmetz
Rolf
R
Jansen
Juana
J
Diez
Ronald
R
Frank
Florenz
F
Sasse
Andreas
A
Meyerhans
D019380:Anti-HIV Agents / Q000302:isolation & purification* / Q000494:pharmacology*; D004351:Drug Resistance; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D009231:Myxococcales / Q000737:chemistry*
D019380:Anti-HIV Agents