Recent advances in the biology and drug targeting of malaria parasite aminoacyl-tRNA synthetases

Khan, Sameena

doi:10.1186/s12936-016-1247-0

Cited by 25 publications

(18 citation statements)

References 56 publications

(174 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These include isoprenoid precursor biosynthesis, fatty acid biosynthesis, Fe-S cluster assembly, and heme biosynthesis (13)(14)(15)(16). The apicoplast is thus indispensable, and either genetic or pharmaceutical perturbation of its activities kills parasites, making the apicoplast a valid drug target (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30).…”

mentioning

confidence: 99%

Validation of Putative Apicoplast-Targeting Drugs Using a Chemical Supplementation Assay in Cultured Human Malaria Parasites

Uddin

McFadden

Goodman

2018

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Malaria parasites contain a relict plastid, the apicoplast, which is considered an excellent drug target due to its bacterial-like ancestry. Numerous parasiticidals have been proposed to target the apicoplast, but few have had their actual targets substantiated. Isopentenyl pyrophosphate (IPP) production is the sole required function of the apicoplast in the blood stage of the parasite life cycle, and IPP supplementation rescues parasites from apicoplast-perturbing drugs. Hence, any drug that kills parasites when IPP is supplied in culture must have a nonapicoplast target. Here, we use IPP supplementation to discriminate whether 23 purported apicoplast-targeting drugs are on- or off-target. We demonstrate that a prokaryotic DNA replication inhibitor (ciprofloxacin), several prokaryotic translation inhibitors (chloramphenicol, doxycycline, tetracycline, clindamycin, azithromycin, erythromycin, and clarithromycin), a tRNA synthase inhibitor (mupirocin), and two IPP synthesis pathway inhibitors (fosmidomycin and FR900098) have apicoplast targets. Intriguingly, fosmidomycin and FR900098 leave the apicoplast intact, whereas the others eventually result in apicoplast loss. Actinonin, an inhibitor of bacterial posttranslational modification, does not produce a typical delayed-death response but is rescued with IPP, thereby confirming its apicoplast target. Parasites treated with putative apicoplast fatty acid pathway inhibitors could not be rescued, demonstrating that these drugs have their primary targets outside the apicoplast, which agrees with the dispensability of the apicoplast fatty acid synthesis pathways in the blood stage of malaria parasites. IPP supplementation provides a simple test of whether a compound has a target in the apicoplast and can be used to screen novel compounds for mode of action.

show abstract

mentioning

confidence: 99%

Validation of Putative Apicoplast-Targeting Drugs Using a Chemical Supplementation Assay in Cultured Human Malaria Parasites

Uddin

McFadden

Goodman

2018

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…These comparisons suggest that there are opportunities to arrive at high affinity Pf TyrRS inhibitors with good selectivity. This is extra interesting since Kahn [18] has recently emphasized the opportunities of TyrRS as a drug target for malaria.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, Plasmodium falciparum prolyl-tRNA synthetase, lysyl-tRNA synthetase and threonyl-tRNA synthetase are inhibited by the natural products halofuginone, cladosporin and borrelidin, respectively [12, 16, 17]. These compounds have also inhibitory effects on malaria parasite growth in vitro or in vivo [18]. Here we focus on tyrosyl-tRNA synthetase (TyrRS) from L donovani.…”

Section: Introductionmentioning

confidence: 99%

Leishmania donovani tyrosyl-tRNA synthetase structure in complex with a tyrosyl adenylate analog and comparisons with human and protozoan counterparts

et al. 2017

View full text Add to dashboard Cite

The crystal structure of Leishmania donovani tyrosyl-tRNA synthetase (LdTyrRS) in complex with a nanobody and the tyrosyl adenylate analog TyrSA was determined at 2.75 Å resolution. Nanobodies are the variable domains of camelid heavy chain-only antibodies. The nanobody makes numerous crystal contacts and in addition reduces the flexibility of a loop of LdTyrRS. TyrSA is engaged in many interactions with active site residues occupying the tyrosine and adenine binding pockets. The LdTyrRS polypeptide chain consists of two pseudo-monomers, each consisting of two domains. Comparing the two independent chains in the asymmetric unit reveals that the two pseudo-monomers of LdTyrRS can bend with respect to each other essentially as rigid bodies. This flexibility might be useful in the positioning of tRNA for catalysis since both pseudo-monomers in the LdTyrRS chain are needed for charging tRNATyr. An “extra pocket” (EP) appears to be present near the adenine binding region of LdTyrRS. Since this pocket is absent in the two human homologous enzymes, the EP provides interesting opportunities for obtaining selective drugs for treating infections caused by L. donovani, a unicellular parasite causing visceral leishmaniasis, or kala azar, which claims 20,000 to 30,000 deaths per year. Sequence and structural comparisons indicate that the EP is a characteristic which also occurs in the active site of several other important pathogenic protozoa. Therefore, the structure of LdTyrRS could inspire the design of compounds useful for treating several different parasitic diseases.

show abstract

“…P. falciparum has 37 aaRS genes, which encodes 36 aaRS enzymes ( 12 ). Of the 36 aaRSs, 16 are exclusively present in cytoplasm, 15 are exclusive to apicoplast, and four are shared by cytoplasm and apicoplast ( 13 ). These enzymes are all indispensable for parasite growth and survival.…”

Section: Introductionmentioning

confidence: 99%

Inhibition ofPlasmodium falciparumLysyl-tRNA synthetase via an anaplastic lymphoma kinase inhibitor

Zhou

Huang

Zheng

et al. 2020

Nucleic Acids Research

View full text Add to dashboard Cite

Aminoacyl-tRNA synthetases are attractive targets for the development of antibacterial, antifungal, antiparasitic agents and for the treatment of other human diseases. Lysyl-tRNA synthetase (LysRS) from this family has been validated as a promising target for the development of antimalarial drugs. Here, we developed a high-throughput compatible assay and screened 1215 bioactive compounds to identify Plasmodium falciparum cytoplasmic LysRS (PfLysRS) inhibitor. ASP3026, an anaplastic lymphoma kinase inhibitor that was used in clinical trials for the treatment of B-cell lymphoma and solid tumors, was identified as a novel PfLysRS inhibitor. ASP3026 suppresses the enzymatic activity of PfLysRS at nanomolar potency, which is >380-fold more effective than inhibition of the human counterpart. In addition, the compound suppressed blood-stage P. falciparum growth. To understand the molecular mechanism of inhibition by ASP3026, we further solved the cocrystal structure of PfLysRS-ASP3026 at a resolution of 2.49 Å, providing clues for further optimization of the compound. Finally, primary structure-activity relationship analyses indicated that the inhibition of PfLysRS by ASP3026 is highly structure specific. This work not only provides a new chemical scaffold with good druggability for antimalarial development but also highlights the potential for repurposing kinase-inhibiting drugs to tRNA synthetase inhibitors to treat human diseases.

show abstract

Recent advances in the biology and drug targeting of malaria parasite aminoacyl-tRNA synthetases

Cited by 25 publications

References 56 publications

Validation of Putative Apicoplast-Targeting Drugs Using a Chemical Supplementation Assay in Cultured Human Malaria Parasites

Validation of Putative Apicoplast-Targeting Drugs Using a Chemical Supplementation Assay in Cultured Human Malaria Parasites

Leishmania donovani tyrosyl-tRNA synthetase structure in complex with a tyrosyl adenylate analog and comparisons with human and protozoan counterparts

Inhibition ofPlasmodium falciparumLysyl-tRNA synthetase via an anaplastic lymphoma kinase inhibitor

Contact Info

Product

Resources

About