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THIOL METABOLISM IN LEISHMANIA AND ITS POTENTIAL USE FOR LEISHMANIASIS THERAPY

IBMC - Institute for Molecular and Cell Biology
Project classification

Scientific area

1.6 Biological sciences (Medical sciences go to scientific area 3.n; Agricultural sciences go to scientific area 4.n)

Discipline(s)

Biochemistry and molecular biology

Project description

Project title

THIOL METABOLISM IN LEISHMANIA AND ITS POTENTIAL USE FOR LEISHMANIASIS THERAPY

Scientific Coordinator's name:

Ana M. Tomás

Scientific Coordinator's e-mail:

atomas@ibmc.up.pt

Principal R&D Unit:

Molecular Parasitology

Other R&D Units involved in the project:

Other R&D units involved in the project

Project keyword(s)

Leishmania; Trypanosomatids; parasite; trypanothione; redox; drug development

Short abstract and comments

Leishmaniasis is a major health and veterinary concern. There is no satisfactory vaccine or treatment for leishmaniasis as all anti-parasitic drugs available suffer from drawbacks, namely host toxicity, complicated regimen of administration, high costs and drug resistance. Redox metabolism is dependent on a conjugate of glutathione and spermidine known as trypanothione [T(SH)2], and not, as in the parasite’s hosts, on glutathione. T(SH)2 is the main thiol of trypanosomatids being fundamental for preservation of their intracellular redox homeostasis and, directly or indirectly, required for a number of essential processes, e.g. peroxide (ROOH, ONNO-) metabolism, nuclear and mitochondrial DNA replication and detoxification of oxoaldehydes. Impelled by the possibility that molecules interacting with this thiol might provide adequate drug targets, we are identifying and characterizing parasite proteins involved in T(SH)2-dependent processes. Trypanothione synthetase (responsible for T(SH)2 synthesis), tryparedoxin [a thioredoxin-like oxidoreductase that transfers reducing equivalents from T(SH)2 to other proteins] and 2-cysteine peroxiredoxins have all been shown essential to the parasite and to infection; some of these are also known to be druggable. The three proteins are, thus, valid drug targets which we are now interested in exploting. For this, we are seeking partners with expertise in areas of drug development against trypanosomatids. Additional Leishmania potential targets, also redox proteins, are currently being studied.

Potential uses/indications

Development of anti-trypanosomatid drugs

Status

Ongoing

Partner Status: Seeking Partners?

Yes

Grant number (QREN, FP7, Eureka, etc)

Grant number (QREN, FP7, Eureka, etc)

Last edited on

2012-12-27 16:58:23

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