Deciphering the interaction of benzoxaborole inhibitor AN2690 with connective polypeptide 1 (CP1) editing domain of Leishmania donovani leucyl-tRNA synthetase

Tandon, Smriti; Manhas, Reetika; Tiwari, Neha; Munde, Manoj; Vijayan, Ramachandran; Gourinath, S.; Muthuswami, Rohini; Madhubala, Rentala

doi:10.1007/s12038-020-00031-8

Cited by 6 publications

(5 citation statements)

References 42 publications

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“…These targets have been well validated and a number of them are now structurally characterized 105 , 107 , 108 . The tRNA synthetase class also appears to be an important target class in other pathogens such as Mycobacterium tuberculosis 109 , Leishmania species 110 , 111 and T. gondii 112 , 113 , and tool compounds show specificity despite orthologs existing in humans. The high level of species selectivity might be achieved because, in humans, tRNA synthetases are part of multiprotein complexes and the enzyme active site is less accessible and thus less druggable.…”

Section: Approaches To Antimalarial Drug Discoverymentioning

confidence: 99%

Antimalarial drug discovery: progress and approaches

Siqueira-Neto,

Wicht,

Chibale

et al. 2023

Nat Rev Drug Discov

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Recent antimalarial drug discovery has been a race to produce new medicines that overcome emerging drug resistance, whilst considering safety and improving dosing convenience. Discovery efforts have yielded a variety of new molecules, many with novel modes of action, and the most advanced are in late-stage clinical development. These discoveries have led to a deeper understanding of how antimalarial drugs act, the identification of a new generation of drug targets, and multiple structure-based chemistry initiatives. The limited pool of funding means it is vital to prioritize new drug candidates. They should exhibit high potency, a low propensity for resistance, a pharmacokinetic profile that favours infrequent dosing, low cost, preclinical results that demonstrate safety and tolerability in women and infants, and preferably the ability to block Plasmodium transmission to Anopheles mosquito vectors. In this Review, we describe the approaches that have been successful, progress in preclinical and clinical development, and existing challenges. We illustrate how antimalarial drug discovery can serve as a model for drug discovery in diseases of poverty.

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Section: Approaches To Antimalarial Drug Discoverymentioning

confidence: 99%

Antimalarial drug discovery: progress and approaches

Siqueira-Neto,

Wicht,

Chibale

et al. 2023

Nat Rev Drug Discov

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“…A new study demonstrated that CP1 domain of Ld LeuRS plays a pivotal role in aminoacylation activities as well. Moreover, with the help of isothermal titration calorimetry, the high binding affinity of AN2690 for CP1 domain could be noticed . With the aforementioned knowledge, it could be deduced that the CP1 domain is essential for the proper functioning of LeuRS.…”

Section: Research Accomplished On Trypanosomatid Aminoacyl Trna Synth...mentioning

confidence: 93%

“…Moreover, with the help of isothermal titration calorimetry, the high binding affinity of AN2690 for CP1 domain could be noticed. 42 With the aforementioned knowledge, it could be deduced that the CP1 domain is essential for the proper functioning of LeuRS. Of the inhibitors designed against trypanosomatid LeuRS, the compounds carrying the thiourea group have posed some of the major drawbacks such as its low solubility and toxicity.…”

Section: Research Accomplished On Trypanosomatid Aminoacyl Trna Synth...mentioning

confidence: 99%

Aminoacyl tRNA Synthetases: Implications of Structural Biology in Drug Development against Trypanosomatid Parasites

Nasim

Qureshi

2023

ACS Omega

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The ensemble of aminoacyl tRNA synthetases is regarded as a key component of the protein translation machinery. With the progressive increase in structure-based studies on tRNA synthetase-ligand complexes, the detailed picture of these enzymes is becoming clear. Having known their critical role in deciphering the genetic code in a living system, they have always been chosen as one of the important targets for development of antimicrobial drugs. Later on, the role of aminoacyl tRNA synthetases (aaRSs) on the survivability of trypanosomatids has also been validated. It became evident through several gene knockout studies that targeting even one of these enzymes affected parasitic growth drastically. Such successful studies have inspired researchers to search for inhibitors that could specifically target trypanosomal aaRSs, and their never-ending efforts have provided fruitful results. Taking all such studies into consideration, these macromolecules of prime importance deserve further investigation for the development of drugs that cure spectrum of infections caused by trypanosomatids. In this review, we have compiled advancements of over a decade that have taken place in the pursuit of devising drugs by using trypanosomatid aaRSs as a major target of interest. Several of these inhibitors work on an exemplary low concentration range without posing any threat to the mammalian cells which is a very critical aspect of the drug discovery process. Advancements have been made in terms of using structural biology as an important tool to analyze the architecture of the trypanosomatids aaRSs and concoction of inhibitors with augmented specificities toward their targets. Some of the inhibitors that have been tested on other parasites successfully but their efficacy has so far not been validated against these trypanosomatids have also been appended.

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“…9078 extracts) Brugia malayi Pretransfer editing site a Yu et al., 2012 ( 30 ) Adipostatins A-D (from Streptomyces sp. 4875 extracts) Brugia malayi Pretransfer editing site a Rateb et al., 2015 ( 31 ) HisRS 15 fragments Trypanosoma cruzi Auxiliary site Koh et al., 2015 ( 33 ) IleRS apicoplast Mupirocin Plasmodium falciparum Active site a Istvan et al., 2011 ( 35 ) IleRS Thiaisoleucine Plasmodium falciparum Active site a Istvan et al., 2011 ( 35 ) NSC70422 (Ile-AMP analog) Trypanosoma brucei Active site a Cestari and Stuart 2013 ( 36 ) LeuRS Benzoxaborole derivatives Trypanosoma brucei Post-transfer editing site Ding et al., 2011 ( 37 ) 2-Pyrrolinone derivatives Trypanosoma brucei Active site (predicted; 3D model of active site) Zhao et al., 2012 ( 40 ) N-(4-sulfamoylphenyl)thioureas derivatives Trypanosoma brucei Active site (predicted; 3D model of active site) Zhang et al., 2013 ( 41 ) 3,5-dicaffeoylquinic acid and derivatives Giardia lamblia Active site a Zhang et al., 2012 ( 42 ) AN2690 Leishmania donovani Active site a Minhas et al., 2018 ( 39 ), Tandon et al., 2020 ( ...…”

Section: Inhibitors Against Parasite Aminoacyl-trna Synthetasesmentioning

confidence: 99%

“…Further, ex vivo growth was inhibited at low micromolar IC 50 s with negligible host toxicity ( Table 1 ) ( 37 ). Similarly, the Connective Polypeptide 1 domain of L. donovani LeuRS was critical for editing the mischarged tRNA and aminoacylation activity ( 38 ). AN2690 also had a low-to-moderate affinity to Ld LeuRS (K d = 30 μM) as it inhibits parasite growth in vitro and in vivo in BALB/c mice while exhibiting negligible toxicity in host cells ( 39 ).…”

Section: Inhibitors Against Parasite Aminoacyl-trna Synthetasesmentioning

confidence: 99%