The importance of nucleoside hydrolase enzyme (NH) in studies to treatment of Leishmania : A review

Figueroa‐Villar, José Daniel; Sales, Edijane Matos

doi:10.1016/j.cbi.2016.12.004

Cited by 19 publications

(11 citation statements)

References 59 publications

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“…Studies using a family of transition state analogues against the bloodstream form of T. brucei brucei indicated that nucleoside hydrolases are not essential . RNA interference to inhibit expression of IAG-NH, IG-NH, and methylthioadenosine phosphorylase did not induce purine starvation.…”

Section: Nucleoside Hydrolasesmentioning

confidence: 85%

“…Studies using a family of transition state analogues against the bloodstream form of T. brucei brucei indicated that nucleoside hydrolases are not essential. 99 RNA interference to inhibit expression of IAG-NH, IG-NH, and methylthioadenosine phosphorylase did not induce purine starvation. Nucleoside hydrolases have provided a thorough understanding of reaction mechanism, transition state structure, reaction coordinate motion, and design of transition state analogues but are not suitable drug targets in the Trypanosoma .…”

Section: Nucleoside Hydrolasesmentioning

confidence: 86%

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Enzymatic Transition States and Drug Design

Schramm

2018

Chem. Rev.

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Transition state theory teaches that chemically stable mimics of enzymatic transition states will bind tightly to their cognate enzymes. Kinetic isotope effects combined with computational quantum chemistry provides enzymatic transition state information with sufficient fidelity to design transition state analogues. Examples are selected from various stages of drug development to demonstrate the application of transition state theory, inhibitor design, physicochemical characterization of transition state analogues, and their progress in drug development.

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Section: Nucleoside Hydrolasesmentioning

confidence: 85%

Section: Nucleoside Hydrolasesmentioning

confidence: 86%

Enzymatic Transition States and Drug Design

Schramm

2018

Chem. Rev.

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“…Multiple nucleoside hydrolase enzymes have been identified in Leishmania that catalyzes the degradation of nucleosides, nucleotides, and nucleic acids in the host before entering the parasite purine pools. The external cell surface of L. donovani expresses two membrane-bound 3′-nucleotidases/nucleases [39]. Thus, targeting the purine salvage pathway can be effective to limit parasite growth and infection (Figure 2).…”

Section: Purine Salvage Pathwaymentioning

confidence: 99%

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

Jain¹,

Sahu²,

Kumar³

2022

Preprint

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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 antileishmanial 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.

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“…NHs have been characterized in several trypanosomatids such as Leishmania donovani , L. tropica , L. major , Trypanosoma cruzi , and T. brucei . The absence of NHs in mammals makes these enzymes an ideal target for selective chemotherapy of protozoan infections. , …”

mentioning

confidence: 99%

“…The absence of NHs in mammals makes these enzymes an ideal target for selective chemotherapy of protozoan infections. 8,9 Natural products play an important role in the treatment of parasitic diseases, as exemplified by the antimalarial drug artemisinin from the medicinal plant Artemisia annua and by the anthelmintic drug ivermectin obtained from the bacterium Streptomyces avermitilis, whose discovery rendered the Noble Prize in Physiology and Medicine to Youyou Tu (China), William Campbell (Ireland), and Satoshi O̅ mura (Japan). 10 In recent decades, the potential of medicinal plants in the treatment of leishmaniasis has attracted growing interest within the scientific community.…”

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confidence: 99%

An NMR-Based Chemometric Strategy to Identify Leishmania donovani Nucleoside Hydrolase Inhibitors from the Brazilian Tree Ormosia arborea

et al. 2020

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Nucleoside hydrolases are a strategic target for the development of drugs to treat leishmaniasis, a neglected disease that affects 700 thousand to one million people annually. The present study aimed to identify Leishmania donovani nucleoside hydrolase (LdNH) inhibitors from the leaves of Ormosia arborea, a tree endemic to Brazilian ecosystems, through a strategy based on 1 H NMR analyses and chemometrics. The aqueous EtOH extract of O. arborea leaves inhibited LdNH activity by 95%. The extract was fractionated in triplicate (13 in each step, making a total of 39 fractions). Partial least squares discriminant analysis (PLS-DA) was used to correlate the 1 H NMR spectra of the fractions with their LdNH inhibitory activity and thus to identify the spectral regions associated with the bioactivity. The strategy aimed at isolating the probable bioactive substances and led to two new A-type proanthocyanidins, linked to a p-coumaroyl unit (1 and 2), which appeared as noncompetitive inhibitors of LdNH (IC 50 : 28.2 ± 3.0 μM and 25.6 ± 4.1 μM, respectively). This study confirms the usefulness of the NMR-based chemometric methods to accelerate the discovery of drugs from natural products.

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The importance of nucleoside hydrolase enzyme (NH) in studies to treatment of Leishmania : A review

Cited by 19 publications

References 59 publications

Enzymatic Transition States and Drug Design

Enzymatic Transition States and Drug Design

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

An NMR-Based Chemometric Strategy to Identify Leishmania donovani Nucleoside Hydrolase Inhibitors from the Brazilian Tree Ormosia arborea

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