Chemotherapy and Biochemistry of Leishmania
Abstract
A comparison of the enzymes of the pathogenic protozoa to those of man is of fundamental importance to the search for much needed chemotherapeutic agents. Nucleic acid metabolism in trypanosomatids is unique in several ways: 1) they lack the ability to synthesize purines do novo, depending entirely on the salvage pathway for their supply of purine nucleotides; 2) many of the enzymes involved in nucleic acid biosynthesis either have unusual substrate specificities or unusual subcellular localizations; 3) a large proportion of the DNA which is produced is incorporated into a organelle known as the kineto- plast; and 4) the DNA polymerase isolated from these organisms demonstrates major differences from its mammalian counterpart. There is very little information concerning the DNA and RNA polymerases of Leishmania spp. Our aim has been the isolation and characterization of the DNA and RNA polymerases of Leishmania mexicana and search in vivo and in vitro for inhibitors of these enzymes for chemotherapeutic exploitation. Sinefungin has been found to be a potent antiparasitic agent at levels which are non toxic to mammalian cells. Our laboratory has found that it drastically affects DNA synthesis in Leishmania spp. We are currently investigating its exact mode of action, to aid in rational drug development. We have continued our studies on the mode of action of Formycin B, an antileishmanial purine analogue, and have shown that is is converted to Formycin A and preferentially incorporated into MRNA as opposed to TRNA and RRNA. Keywords: Antileishmanials; Antileishmanial agents.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 1985
- Accession Number
- ADA196459
Entities
People
- Linda L. Nolan
Organizations
- University of Massachusetts Amherst