title: Orally Active and Selective Tubulin Inhibitors as Anti-Trypanosome Agents.
abstract: OBJECTIVE
  There is an urgent need to develop a safe, effective, orally active, and inexpensive therapy for African trypanosomiasis due to the drawbacks of current drugs. Selective tubulin inhibitors have the potential to be promising drug candidates for the treatment of this disease, which is based on the tubulin protein structural difference between mammalian and trypanosome cells. We propose to identify novel tubulin inhibitors from a compound library developed based on the lead compounds that selectively target trypanosomiasis.
  
  
  METHODS
  We used Trypanosoma brucei brucei as the parasite model, and human normal kidney cells and mouse microphage cells as the host model. Growth rates of both trypanosomes and mammalian cells were determined as a means to screen compounds that selectively inhibit the proliferation of parasites. Furthermore, we examined the cell cycle profile of the parasite and compared tubulin polymerization dynamics before and after the treatment using identified compounds. Last, in vivo anti-parasite activities of these compounds were determined in T. brucei-infected mice.
  
  
  RESULTS
  Three compounds were selected that are 100 fold more effective against the growth of T. brucei cells than mammalian cells. These compounds caused cell cycle progression defects in T. brucei cells. Western analyses indicated that these compounds decreased tubulin polymerization in T. brucei cells. The in vivo investigation revealed that these compounds, when admitted orally, inhibited T. brucei cell proliferation in mouse blood. However, they were not potent enough to clear up the infection completely.
  
  
  CONCLUSIONS
  These compounds are promising lead compounds as orally active agents for drug development of anti-trypanosome agents. A more detail structure activity relationship (SAR) was summarized that will be used to guide future lead optimization to improve the selectivity and potency of the current compounds.
authors.affiliation: Department of Biology, Geo. & Env. Sciences, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America.
authors.forename: Vishal
authors.initials: V
authors.lastname: Nanavaty
authors.affiliation: Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America.
authors.forename: Rati
authors.initials: R
authors.lastname: Lama
authors.affiliation: Department of Biology, Geo. & Env. Sciences, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America.
authors.forename: Ranjodh
authors.initials: R
authors.lastname: Sandhu
authors.affiliation: Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhong
authors.affiliation: Department of Biology, Geo. & Env. Sciences, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kulman
authors.affiliation: Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America.
authors.forename: Viharika
authors.initials: V
authors.lastname: Bobba
authors.affiliation: Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America.
authors.forename: Anran
authors.initials: A
authors.lastname: Zhao
authors.affiliation: Department of Biology, Geo. & Env. Sciences, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America.|Center for Gene Regulation in Health and Disease, College of Sciences & Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America.
authors.forename: Bibo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America.|Center for Gene Regulation in Health and Disease, College of Sciences & Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America.
authors.forename: Bin
authors.initials: B
authors.lastname: Su
mesh_terms: D000284:Administration, Oral; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D015800:Protozoan Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000009:adverse effects / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy; D050257:Tubulin Modulators / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D050257:Tubulin Modulators