Plasmodium PK9 Inhibitors Promote Growth of Liver-Stage Parasites

Raphemot, Rene; Eubanks, Amber L.; Toro-Moreno, Maria; Geiger, Rechel; Hughes, Philip F.; Lu, Kuan-Yi; Haystead, Timothy; Derbyshire, Emily R.

doi:10.1016/j.chembiol.2018.11.003

Cited by 13 publications

(21 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pf PK9 is another orphan kinase, essential for the blood-stage [ 17 ], with currently only one known phosphorylation target: the E2 ubiquitin-conjugating enzyme 13 ( Pf UBC13) [ 99 ]. The human homolog, Hs UBC13, is involved in DNA repair and immune responses [ 100 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments

2020

View full text Add to dashboard Cite

Recent progress in reducing malaria cases and ensuing deaths is threatened by factors like mutations that induce resistance to artemisinin derivatives. Multiple drugs are currently in clinical trials for malaria treatment, including some with novel mechanisms of action. One of these, MMV390048, is a plasmodial kinase inhibitor. This review lists the recently developed molecules which target plasmodial kinases. A systematic review of the literature was performed using CAPLUS and MEDLINE databases from 2005 to 2020. It covers a total of 60 articles and describes about one hundred compounds targeting 22 plasmodial kinases. This work highlights the strong potential of compounds targeting plasmodial kinases for future drug therapies. However, the majority of the Plasmodium kinome remains to be explored.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Pf PK9 inhibitors have only been explored by Raphemot et al [ 100 ]. Starting from a screening of 3,200 molecules, authors discovered that taketinib ( 85 ), an inhibitor of Hs TAK1, was an inhibitor of Pf PK9 ( Table 11 ).…”

Section: Discussionmentioning

confidence: 99%

Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments

2020

View full text Add to dashboard Cite

show abstract

“…P. falciparum 3D7 parasite (MRA-102) was obtained from BEI Resources and cultured as previously described (Radfar et al, 2009; Raphemot et al, 2019). Parasites were synchronized with 5 % D-sorbitol (Sigma) at 37ºC for 10 minutes and adjusted to 2 % parasitemia and 2 % hematocrit prior to the assay.…”

Section: Methodsmentioning

confidence: 99%

A Systematic Analysis of Mosquito-Microbiome Biosynthetic Gene Clusters Reveals Antimalarial Siderophores that Reduce Mosquito Reproduction Capacity

Ganley

Pandey

Sylvester³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

21 22 23 24 25 26 2 ABSTRACT 27Advances in infectious disease control strategies through genetic manipulation of insect 28 microbiomes have heightened interest in microbially produced small molecules within 29 mosquitoes. Herein, 33 mosquito-associated bacterial genomes were mined and over 700 30 putative biosynthetic gene clusters (BGCs) were identified, 135 of which belong to known 31 classes of BGCs. After an in-depth analysis of the 135 BGCs, iron-binding siderophores 32 were chosen for further investigation due to their high abundance and well-characterized 33 bioactivities. Through various metabolomic strategies, eight siderophore scaffolds were 34 identified in six strains of mosquito-associated bacteria. Among these, serratiochelin A 35 and pyochelin were found to reduce female Anopheles gambiae overall fecundity likely by 36 lowering their blood feeding rate. Serratiochelin A and pyochelin were further found to 37 inhibit the Plasmodium parasite asexual blood and liver stages in vitro. Our work supplies 38 a bioinformatic resource for future mosquito microbiome studies and highlights an 39 understudied source of bioactive small molecules. 40 41 KEYWORDS 42 Mosquito-Microbiome; Biosynthetic Gene Clusters; Siderophores; Anopheles; 43 Plasmodium 44 45 46 100 transmit avian malaria, P. gallinaceum (Alavi et al., 2003), as well as human infectious 101 agents including dengue virus, Zika virus, and others (2016). As a relevant disease vector,102 Aedes-associated bacteria were also included in our data set. Due to the limited amount 103 of genome sequencing data on mosquito-associated bacteria, especially when compared 104 5 to human microbiomes, our sample size is smaller than analogous studies (Aleti et al., 105 2019; Donia et al., 2014; Helfrich et al., 2018), however this enabled an in-depth 106 bioinformatic analysis. Despite this size, our data set well-represents the unique gut 107 microbiome of mosquitoes. Our previous metagenomic study demonstrated that within the 108 gut microbiota of field-caught A. gambiae mosquitoes four days post blood-meal, 5 109 bacterial genera (Serratia, Elizabethkingia, Acinetobacter, Enterobacter, and 110 Pseudomonas) constitute 84 % of the 16S rRNA reads (Wang et al., 2011), all of which 111 are represented within our sample set. 112 A phylogenetic tree comparing the 33 bacterial strains was generated (Figure 113 1). The best-represented bacterial phylum in our sample set was Proteobacteria (16 γ-114 Proteobacteria, 1 β-Proteobacteria, and 3 α-Proteobacteria), consistent with reports 115 showing Proteobacteria are often the overwhelming microbial phylum in the midgut of 116 field-caught Anopheles mosquitoes (Wang et al., 2011). Species in the Bacteroidetes 117 phylum, which include Elizabethkingia spp., were the second most recurrent group (4 118 Elizabethkingia spp. and 1 Sphingobacterium sp.) in our analysis. Elizabethkingia spp. are 119 well-established mosquito symbionts that are the dominant species within midguts 4-and 120 7-days post-blood meal (PBM) as well as 7-day...

show abstract

“…Only one study has been published thus far with regards to inhibitor development for Pf PK9. Screening of a kinase-targeted library against Pf PK9 identified takinib (83, Figure 32), which demonstrated low micromolar binding affinity (K d(app) : 0.46 µM) for Pf PK9 [177]. Takinib is a potent inhibitor (IC 50 : 9.5 nM, [178]) of human mitogen-activated protein kinase kinase kinase 7 (MAP3K7, or more commonly referred to as TAK1).…”

Section: Pf Pk9mentioning

confidence: 99%

An Update on Development of Small-Molecule Plasmodial Kinase Inhibitors

et al. 2020

View full text Add to dashboard Cite

Malaria control relies heavily on the small number of existing antimalarial drugs. However, recurring antimalarial drug resistance necessitates the continual generation of new antimalarial drugs with novel modes of action. In order to shift the focus from only controlling this disease towards elimination and eradication, next-generation antimalarial agents need to address the gaps in the malaria drug arsenal. This includes developing drugs for chemoprotection, treating severe malaria and blocking transmission. Plasmodial kinases are promising targets for next-generation antimalarial drug development as they mediate critical cellular processes and some are active across multiple stages of the parasite’s life cycle. This review gives an update on the progress made thus far with regards to plasmodial kinase small-molecule inhibitor development.

show abstract

Plasmodium PK9 Inhibitors Promote Growth of Liver-Stage Parasites

Abstract: Highlights d PfPK9-binding compounds were discovered d PfPK9-binding compounds inhibit K63-linked ubiquitination in Plasmodium d Takinib and PfPK9-selective HS220 inhibit liver-stage Plasmodium d Takinib and PfPK9-selective HS220 increase liver-stage parasite size

Cited by 13 publications

References 44 publications

Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments

Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments

A Systematic Analysis of Mosquito-Microbiome Biosynthetic Gene Clusters Reveals Antimalarial Siderophores that Reduce Mosquito Reproduction Capacity

An Update on Development of Small-Molecule Plasmodial Kinase Inhibitors

Contact Info

Product

Resources

About