Altenusin, a biphenyl isolated from the endophytic fungus Alternaria sp., inhibits trypanothione reductase from Trypanosoma cruzi

• Published in: FEMS microbiology letters Vol. 285; no. 2; pp. 177 - 182
• Main Authors: Cota, Betania Barros, Rosa, Luiz Henrique, Caligiorne, Rachel Basques, Rabello, Ana Lúcia Teles, Almeida Alves, Tânia Maria, Rosa, Carlos Augusto, Zani, Carlos Leomar
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.08.2008; Blackwell Publishing Ltd; Blackwell; Oxford University Press
• Subjects: altenusin; Alternaria; Alternaria - chemistry; Alternaria - classification; Alternaria - genetics; Alternaria - isolation & purification; Alternaria sp; Animals; Asteraceae - microbiology; Biodiversity; Biological and medical sciences; Biphenyl; Biphenyl Compounds - isolation & purification; Biphenyl Compounds - pharmacology; Chemotherapy; DNA, Fungal - chemistry; DNA, Fungal - genetics; DNA, Ribosomal Spacer - genetics; Drug development; Endophytes; endophytic fungus; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; Etiology; Flora; Fractionation; Fundamental and applied biological sciences. Psychology; Fungi; Growth, nutrition, metabolism, transports, enzymes. Molecular biology; Humans; Inhibitory Concentration 50; Leishmania; Leishmania amazonensis; Leishmaniasis; Microbiology; Molecular Sequence Data; Molecular Structure; Mycology; NADH, NADPH Oxidoreductases - antagonists & inhibitors; Natural products; Oxidative stress; Phylogeny; Protozoa; Reductases; Sequence Analysis, DNA; Trypanosoma; Trypanosoma cruzi; Trypanosoma cruzi - enzymology; Trypanosomiasis; Trypanothione; Trypanothione reductase; Vector-borne diseases; endophytic fungus; trypanothione reductase; altenusin; sp; Kinetoplastida; Protozoa; Enzyme; Alternaria; Biological activity; Trypanosoma cruzi; Fungi; Antiprotozoal agent; Biphenyl; Alternaria sp; Endophyte; Fungi Imperfecti; Oxidoreductases; Leishmania amazonensis; Trypanothione reductase
• ISSN: 0378-1097; 1574-6968
• DOI: 10.1111/j.1574-6968.2008.01221.x

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 μg mL⁻¹. Fractionation of the extract identified altenusin, a biphenyl derivative with an IC₅₀ value of 4.3±0.3 μM 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.