Search for new treatments against Leishmaniasis Cutanea

Claudia Villalobos

Leishmaniasis is a tropical disease that affects at least 200 million people worldwide. However, it has been neglected, and new treatments have not been implemented for several decades.

This circumstance prompted the World Health Organization (WHO) to call for the search for new drugs, leading scientists from the Instituto Politécnico Nacional (IPN) to evaluate different molecules to treat the cutaneous form of the disease.

Observing that the prolonged use of current drugs (pentavalent antimonials) can generate toxic effects in patients, Dr. Lenci Karina Vázquez Jiménez, a researcher at the Center for Genomic Biotechnology (CBG), initiated a project to find new alternatives that, in addition to being effective, have an accessible cost for the population.

Key enzyme

"In addition to the fact that currently used drugs can cause toxicity when used for prolonged periods, some of them have low efficacy, restricted use, and high cost," stated Dr. Vázquez Jiménez, who considered it necessary to overcome these difficulties and delve into research that leads to alternatives that are more effective against the protozoan parasite Leishmania and safer for patients.

The young scientist emphasized that, to achieve this objective, a viable approach is to search for pharmacological targets or therapeutic targets. "In this case, we identified enzymes present in the parasite that are essential for its survival, such as those in the glycolysis pathway (through which the infectious agent obtains energy), which we can interfere with to cause the protozoan to die due to lack of energy."

Thus, the triose phosphate isomerase was determined as the key enzyme to inhibit the parasite, which is also produced by humans but with a different structure.

Only two molecules

After defining the therapeutic target, Dr. Vázquez Jiménez, advised by scientists Gildardo Rivera Sánchez from the CBG and María Esther Ramírez Moreno from the National School of Medicine and Homeopathy (ENMH), used computational techniques to access a platform of benzimidazole-derived compounds to perform a molecular docking study of 75 million molecules on the triose phosphate isomerase enzyme of the parasite.

"From the 75 million, we selected the 175 molecules with the best pharmacokinetic, pharmacodynamic, and gastrointestinal profiles since these characteristics are necessary for the consumption of oral drugs. After conducting molecular docking assays, 10 molecules were selected for molecular dynamics studies, and it was determined that compounds E2 and P9 showed the best stability as potential inhibitors of triose phosphate isomerase," she warned.

She explained that after computationally assessing the efficacy of both compounds, a search was conducted to verify their availability in the market. In this way, both molecules were evaluated in vitro (directly on the parasite), and it was found that compound P9 was the most effective since it was determined to cause lysis (cellular deterioration due to membrane damage).

Structural difference

Due to the structural differences between the triose phosphate isomerase enzyme of the parasite and that of humans, compound P9 only acts on the pathogen's enzyme, which suggests that it does not cause direct harm to humans and could be a viable alternative to be used as a potential drug to treat leishmaniasis without causing side effects in people.

"Although the preliminary results so far are promising, it is very important to further deepen the research before reaching the clinical stage," stated the scientist from the Center for Genomic Biotechnology.

Transmission and distribution

Cutaneous leishmaniasis is transmitted to humans through the bite of the female sandfly or black fly, which needs to ingest blood to produce eggs. The infection affects the skin and mucous membranes, resulting in the appearance of a cutaneous lesion after an incubation period of 2 weeks to 2 months. The sores usually begin at the site of the sandfly bite.

In children, it is common to find lesions on the face and exposed areas of the limbs. Some cutaneous lesions heal spontaneously in several months, but most ulcers have a chronic course lasting months or years.

According to official data from the Ministry of Health (SS), this disease generally occurs in agricultural areas where cocoa, coffee, or chicle trees are grown and harvested (hence its name "chiclero's ulcer").

The at-risk population is distributed in 13 states within three geographical areas: Gulf Region (Veracruz, Tabasco, Campeche, Quintana Roo, and Yucatán), Pacific Region (Chiapas, Guerrero, Jalisco, Nayarit, Oaxaca, and Sinaloa), and Central Region (Morelos and Puebla).

This disease generally occurs in agricultural areas where cocoa, coffee, or chicle trees are grown and harvested.

PREVENTION

If there are cases of Leishmaniasis where you live, it is necessary to:

• Seek medical attention at the nearest health unit or notification center if ulcerative lesions appear on any part of the body and do not heal (for more than a month).

• Use repellents, long-sleeved shirts, and cover your ears.

• Install fine-mesh mosquito nets on doors and windows and use a bed net for sleeping.

• Avoid sleeping outdoors.

• Keep the house and the area surrounding it free of weeds.

Selección Gaceta Politécnica #162. 2023, May 31st. IPN Imagen Institucional: Read the full magazine in spanish here