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Titolo:
Trypanosoma brucei CTP synthetase: A target for the treatment of African sleeping sickness
Autore:
Hofer, A; Steverding, D; Chabes, A; Brun, R; Thelander, L;
Indirizzi:
Umea Univ, Dept Med Biosci, SE-90187 Umea, Sweden Umea Univ Umea Sweden SE-90187 v, Dept Med Biosci, SE-90187 Umea, Sweden Univ Heidelberg, Dept Parasitol, D-69120 Heidelberg, Germany Univ Heidelberg Heidelberg Germany D-69120 , D-69120 Heidelberg, Germany Swiss Trop Inst, CH-4002 Basel, Switzerland Swiss Trop Inst Basel Switzerland CH-4002 st, CH-4002 Basel, Switzerland
Titolo Testata:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
fascicolo: 11, volume: 98, anno: 2001,
pagine: 6412 - 6416
SICI:
0027-8424(20010522)98:11<6412:TBCSAT>2.0.ZU;2-N
Fonte:
ISI
Lingua:
ENG
Soggetto:
CULTIVATION; METABOLISM; SALVAGE; CULTURE; GROWTH; FORMS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
26
Recensione:
Indirizzi per estratti:
Indirizzo: Hofer, A Umea Univ, Dept Med Biosci, SE-90187 Umea, Sweden Umea Univ Umea Sweden SE-90187 ed Biosci, SE-90187 Umea, Sweden
Citazione:
A. Hofer et al., "Trypanosoma brucei CTP synthetase: A target for the treatment of African sleeping sickness", P NAS US, 98(11), 2001, pp. 6412-6416

Abstract

The drugs in clinical use against African sleeping sickness are toxic, costly, or inefficient. We show that Trypanosoma brucei, which causes this disease, has very low levels of CTP, which are due to a limited capacity for de novo synthesis and the lack of salvage pathways. The CTP synthetase inhibitors 6-diazo-5-oxo-L-norleucine (DON) and alpha -amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin) reduced the parasite CTP levels even further and inhibited trypanosome proliferation in vitro and in T. brucei-infected mice. In mammalian cells, DON mainly inhibits de novo purine biosynthesis, a pathway lacking in trypanosomes. We could rescue DON-treated human and mouse fibroblasts by the addition of the purine base hypoxanthine to the growth medium. For treatment of sleeping sickness, we propose the use of CTP synthetase inhibitors alone or in combination with appropriate nucleosides or bases.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/01/21 alle ore 03:47:08