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UniProt release 2020_06

Published December 2, 2020

Headline

Venoms, gold mines for new antiprotozoal drugs

Neglected diseases are typically tropical infections, which are common in low-income populations in developing regions of Africa, Asia, and the Americas and affect more than one billion people. Among them, Chagas disease, also known as American trypanosomiasis, affects an estimated 6 to 7 million people worldwide. This disease is caused by the parasitic protozoan Trypanosoma cruzi. The disease is typically transmitted to humans and other mammals by the bite of infected triatomine insects, also known as kissing bugs or vampire bugs. Once inside the host, the protozoan invades cells near the site of inoculation, where it differentiates into an intracellular parasitic form called the amastigote. Amastigotes multiply, differentiate into trypomastigotes which burst the host cell, and are released into the circulation, from where they can invade a variety of tissues and repeat the same infectious cycle in new sites. In the early stage of infection, symptoms are mild, if any, and may include fever, swollen lymph nodes, headaches, or swelling at the site of the bite. After a few weeks, untreated individuals enter the chronic phase of disease and most do not show any further symptoms. However, in the long term (10-30 years after the initial illness), chronic infection may lead to cardiomyopathies, digestive tract pathologies, and up to 10% of people experience nerve damage.

There are only two drugs currently used to treat Chagas disease, benznidazole and nifurtimox. Unfortunately they are rarely beneficial during the chronic phase of the disease and can cause severe adverse effects. Moreover, resistance to these drugs is emerging in various parasitic strains. In this context, the observation that crude venom from a Brazilian ant called Dinoponera quadriceps had antichagasic activity and low toxicity in vitro offers one hope for the development of alternative therapies for Chagas disease. A venom component bearing this activity was identified as a 23-amino acid long peptide, called M-poneratoxin-Dq3a (M-PONTX-Dq3a). This peptide induced trypanosome necrosis and acted on the three parasitic forms: epimastigote (found in the gut of the vector insect), infectious trypomastigote and intracellular amastigote, suggesting that M-PONTX-Dq3a could be beneficial during the chronic phase of the infection. These effects were observed at concentrations low enough to avoid any toxicity for mammalian host cells contrary to benznidazole.

Ants are not the only organisms that can give us a hand in the fight against T. cruzi. Snakes, such as Bothrops atrox and Crotalus durissus terrificus, and wasps, such as Polybia paulista, have also been shown to produce antichagasic toxins. All venom toxins characterized so far were active against the three T. cruzi forms at concentrations that did not harm host cells. Their modes of action could differ, but all exhibited a high selectivity index (a ratio that measures the window between cytotoxicity and antimicrobial activity), which clearly qualifies them for further study in the development of new drugs.

Animal toxins with antichagasic properties have been manually annotated in UniProtKB/Swiss-Prot and are publicly available as of this release.

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