Targeting the Wolbachia Cell Division Protein FtsZ as a New Approach for Antifilarial Therapy

Filarial nematode parasites are responsible for a number of devastating diseases in humans and animals. These include lymphatic filariasis and onchocerciasis that afflict 150 million people in the tropics and threaten the health of over one billion. The parasites possess intracellular bacteria, Wolbachia, which are needed for worm survival. Clearance of these bacteria with certain antibiotics leads to parasite death. These findings have pioneered the approach of using antibiotics to treat and control filarial infections. In the present study, we have investigated the cell division process in Wolbachia for new drug target discovery. We have identified the essential cell division protein FtsZ, which has a GTPase activity, as an attractive Wolbachia drug target. We describe the molecular characterization and catalytic properties of the enzyme and demonstrate that the GTPase activity is inhibited by the natural product, berberine, and small molecule inhibitors identified from a high-throughput screen. We also found that berberine was effective in reducing motility and reproduction in B. malayi parasites in vitro. Our results should facilitate the discovery of selective inhibitors of FtsZ as a novel antibiotic approach for controlling filarial infection

Evaluation of In-111-labeled Anginex as Potential SPECT Tracer for Imaging of Tumor Angiogenesis

Angiogenesis is a prerequisite for solid tumors to grow and metastasize, providing oxygen and nutrients to the tumor site. The protein galectin-1 has been identified to be overexpressed on tumor vasculature and represents an interesting target for anti-angiogenic therapy, as well as in molecular imaging. Therefore, the galectin-1-binding peptide Anginex was modified for radiolabeling using 111In. In vitro, 111In-Ax showed significantly more binding to galectin-1-positive EC-RF24 and MDA-MB-231-LITG cells than to galectin-1-negative LS174T cells and association with ECRF24 cells was reduced in the presence of excess native Anginex. However, ex vivo biodistribution profiles showed little tumor uptake of 111In-Ax and extensive accumulation in non-target organs. Although this study shows the ease of modification of the therapeutic peptide Anginex and favorable characteristics in vitro, in vivo assessment of the tracer revealed negligible tumor targeting. Hence, the strategy we employed lends little support for successful noninvasive imaging of tumor angiogenesis using this peptide

Berberine targets assembly of Escherichia coli cell division protein FtsZ

10.1021/bi7018546Biochemistry47103225-3234BICH