Topoisomerases: Target for Antitrypanosomal Therapy

Summary

Principal Investigator: Theresa Shapiro
Abstract: African trypanosomiasis is lethal if not treated and its incidence is increasing. Existing therapies are antique by contemporary standards and no vaccine is available. The DNA topoisomerases are enzymes essential for nucleic acid biosynthesis and cell survival and are proven targets for clinically valuable anti-infective and antitumor drugs. Previous work from this lab has established that topoisomerase inhibitors cause dramatic lesions in nuclear and mitochondrial (kinetoplast) DNA which are directly proportional to cell killing. This is an ongoing project to examine the DNA topoisomerases as targets for antitrypanosomal drug development, and the specific aims are three. First is to study type I enzymes, including the intracellular localization of structurally unique topo IB. This aim also includes the newly identified topoisomerases IA, characterizing their gene sequence and investigating intrace!!ular enzyme function by RNAi silencing. Aim 2 focuses on a previously unrecognized, second type IIA topoisomerase that occurs in trypanosomes: its catalytic features and inhibitor susceptibilities, and the consequences of silencing by RNAi. The third aim is to bring these basic molecular studies closer to the clinic by exploring the structure-activity relationship and selective toxicity of known topoisomerase inhibitors against trypanosomes in vitro. Included are recently discovered inhibitors oftopo IB, as well as topo II inhibitors with representatives currently in clinical trials. Compounds that appear most promising will be evaluated in mice. These studies take a multi-faceted, rational, and tangible approach to the development of much-needed new anti-trypanosomal chemotherapy.
Funding Period: 1990-08-01 - 2009-04-30
more information: NIH RePORT

Top Publications

  1. pmc Potent antitrypanosomal activities of heat shock protein 90 inhibitors in vitro and in vivo
    Kirsten J Meyer
    Department of Pharmacology and Molecular Sciences, The Johns Hopkins UniversitySchool of Medicine, Baltimore, MD, USA
    J Infect Dis 208:489-99. 2013
  2. ncbi Distinct genes encode type II Topoisomerases for the nucleus and mitochondrion in the protozoan parasite Trypanosoma brucei
    Tomasz Kulikowicz
    Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    J Biol Chem 281:3048-56. 2006
  3. ncbi A mitochondrial topoisomerase IA essential for late theta structure resolution in African trypanosomes
    Jane R Scocca
    Division of Clinical Pharmacology, Department of Medicine and of Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
    Mol Microbiol 67:820-9. 2008
  4. pmc Activity of indenoisoquinolines against African trypanosomes
    Rahul P Bakshi
    Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    Antimicrob Agents Chemother 53:123-8. 2009
  5. pmc Newly identified antibacterial compounds are topoisomerase poisons in African trypanosomes
    Sonya C Tang
    Department of Medicine, The Johns Hopkins University School of Medicine, 301 Hunterian Building, 725 North Wolfe Street, Baltimore, MD 21205, USA
    Antimicrob Agents Chemother 54:620-6. 2010

Scientific Experts

Detail Information

Publications5

  1. pmc Potent antitrypanosomal activities of heat shock protein 90 inhibitors in vitro and in vivo
    Kirsten J Meyer
    Department of Pharmacology and Molecular Sciences, The Johns Hopkins UniversitySchool of Medicine, Baltimore, MD, USA
    J Infect Dis 208:489-99. 2013
    ..brucei. These promising results support the use of inhibitors to study Hsp90 function in trypanosomes and to expand current clinical development of Hsp90 inhibitors to include T. brucei...
  2. ncbi Distinct genes encode type II Topoisomerases for the nucleus and mitochondrion in the protozoan parasite Trypanosoma brucei
    Tomasz Kulikowicz
    Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    J Biol Chem 281:3048-56. 2006
    ....
  3. ncbi A mitochondrial topoisomerase IA essential for late theta structure resolution in African trypanosomes
    Jane R Scocca
    Division of Clinical Pharmacology, Department of Medicine and of Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
    Mol Microbiol 67:820-9. 2008
    ..With no close orthologue in humans it also offers a target for the rational development of selectively toxic new antiprotozoal therapies...
  4. pmc Activity of indenoisoquinolines against African trypanosomes
    Rahul P Bakshi
    Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    Antimicrob Agents Chemother 53:123-8. 2009
    ..The indenoisoquinolines provide a promising lead for the development of drugs against sleeping sickness...
  5. pmc Newly identified antibacterial compounds are topoisomerase poisons in African trypanosomes
    Sonya C Tang
    Department of Medicine, The Johns Hopkins University School of Medicine, 301 Hunterian Building, 725 North Wolfe Street, Baltimore, MD 21205, USA
    Antimicrob Agents Chemother 54:620-6. 2010
    ..Both compounds are planar aromatic polycyclic structures that intercalate into and unwind DNA. These findings reinforce the utility of topoisomerase IImt as a target for development of new drugs for African sleeping sickness...