Metabolic Pathways of Leishmania Parasite: Source of Pertinent Drug Targets and Potent Drug Candidates

Abstract

Leishmaniasis is a tropical disease caused by a protozoan parasite Leishmania that is transmitted via infected female sandflies. At present, leishmaniasis treatment mainly counts on chemotherapy. The currently available drugs against leishmaniasis are costly, toxic, with multiple side effects, and limitations in the administration route. The rapid emergence of drug resistance has severely reduced the potency of anti-leishmanial drugs. As a result, there is a pressing need for the development of novel anti-leishmanial drugs with high potency, low cost, acceptable toxicity, and good pharmacokinetics features. Due to the availability of preclinical data, drug repurposing is a valuable approach for speeding up the development of effective anti-leishmanial through pointing to new drug targets in less time, having low costs and risk. Metabolic pathways of this parasite play a crucial role in the growth and proliferation of Leishmania species during the various stages of their life cycle. Based on available genomics/proteomics information, known pathways-based (sterol biosynthetic pathway, purine salvage pathway, glycolysis, GPI biosynthesis, hypusine, polyamine biosynthesis) Leishmania-specific proteins could be targeted with known drugs that were used in other diseases, resulting in finding new promising anti-leishmanial therapeutics. The present review discusses various metabolic pathways of the Leishmania parasite and some drug candidates targeting these pathways effectively that could be potent drugs against leishmaniasis in the future.

Antileishmanial Activity and In Silico Molecular Docking Studies of Malachra alceifolia Jacq. Fractions against Leishmania mexicana Amastigotes

“…1R9J transfers two-carbon glycolaldehyde units from ketose-donors to aldose-acceptor sugars; 1A7K and 1Q50 catalyze oxidation-reduction reactions and provide defense against oxidative stress. 2C34 is central to host-parasite interactions and virulence factors, while 4ITY is involved in cellular growth, survival and robust pathogenesis [ 15 , 55 , 56 , 57 ]. The cysteine peptidases proteins play a crucial role in host cell-parasite interaction, thus affecting host immune response, autophagy, cell death and growth suppressors.…”

GSK-3 kinase a putative therapeutic target in trypanosomatid parasites

“…For example, Artesunate, the most stable derivative of the sesquiterpene lactone artemisinin, which is derived from a Chinese plant, appears to possess anti- Leishmania activity and prevent pain and neuroinflammation induced by L. amazonensis in BALB/c mice. 46 …”

Quantum Dynamics and Bi Metal Force Field Parameterization Yielding Significant Antileishmanial Targets

“…These drugs most commonly target thiol-based redox systems of parasites. The most common and critical pathway, trypanothione metabolic pathway (T­(SH) 2 ), however serves as a suitable target carrying a unique thiol-based metabolic system different from humans. − The substantial role of this pathway in a myriad of reactions comprises defense against oxidative damage, redox, homeostasis, and replication, − presenting itself as suitable for the design of antitrypanosomatid agents. Two widely circulated drug targets, namely, trypanothione synthetase-amidase (TSA) and trypanothione reductase (TR), play a central role in the (T­(SH) 2 ) pathway.…”

“…Two widely circulated drug targets, namely, trypanothione synthetase-amidase (TSA) and trypanothione reductase (TR), play a central role in the (T­(SH) 2 ) pathway. (T­(SH) 2 ) is synthesized from two processes: one is from the reaction of GSH and Spd catalyzed by TSA while the other is the TR-catalyzed TS2 reduction reaction. , Amid continuous efforts after genetic and chemical validation in the design of effective and less toxic inhibitors, multiple studies have proposed chemotherapy with metal-containing compounds. Pentavalent antimonial including sodium stibogluconate and meglumine antimoniate is the most commonly used drug. − Pentavalent antimonial however offers costly and onerous treatment procedures, leading to unsolicited damage done to the body by antimony Sb­(III) along with the possibility of drug resistance. − …”

“…(T(SH) 2 ) is synthesized from two processes: one is from the reaction of GSH and Spd catalyzed by TSA while the other is the TR-catalyzed TS2 reduction reaction. 8,13 Amid continuous efforts after genetic and chemical validation in the design of effective and less toxic inhibitors, multiple studies have proposed chemotherapy with metal-containing compounds. Pentavalent antimonial including sodium stibogluconate and meglumine antimoniate is the most commonly used drug.…”