Altenusin, a biphenyl isolated from the endophytic fungus Alternaria sp., inhibits trypanothione reductase from Trypanosoma cruzi.
Parasitic protozoan species belonging to the genera Trypanosoma and Leishmania are the etiological agents of several diseases in tropical areas of the world, for which there is an urgent need for effective and affordable treatment. In this regard, we are screening the Brazilian biodiversity, especially its flora and mycota, for natural products that could serve as leads for drug development against these diseases. Trypanothione reductase (TR) is an enzyme involved in the protection of Trypanosoma and Leishmania species against oxidative stress, and is considered to be a validated drug target. The endophytic fungus Alternaria sp. (UFMGCB55) was isolated from the plant Trixis vauthieri DC (Asteraceae), known to contain trypanocidal compounds. The organic extract of the culture of Alternaria sp. was able to inhibit TR by 99%, when tested at 20 microg mL(-1). Fractionation of the extract identified altenusin, a biphenyl derivative with an IC50 value of 4.3+/-0.3 microM in the TR assay. This compound is the first in its class to have shown TR inhibitory activity, opening new perspectives for the design of more effective derivatives that could serve as drug leads for new chemotherapeutic agents to treat trypanosomiasis and leishmaniasis.
Cota
Betania Barros
BB
Laboratório de Química de Produtos Naturais, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Brazil.
Rosa
Luiz Henrique
LH
Caligiorne
Rachel Basques
RB
Rabello
Ana Lúcia Teles
AL
Almeida Alves
Tânia Maria
TM
Rosa
Carlos Augusto
CA
Zani
Carlos Leomar
CL
D000528:Alternaria / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000302:isolation & purification; D000818:Animals; D019659:Asteraceae / Q000382:microbiology; D001713:Biphenyl Compounds / Q000302:isolation & purification* / Q000494:pharmacology*; D004271:DNA, Fungal / Q000737:chemistry / Q000235:genetics; D021903:DNA, Ribosomal Spacer / Q000235:genetics; D004791:Enzyme Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D014349:Trypanosoma cruzi / Q000201:enzymology*
D001713:Biphenyl Compounds; D004271:DNA, Fungal; D021903:DNA, Ribosomal Spacer; D004791:Enzyme Inhibitors; C095643:altenusin; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase