Discovery of HDAC inhibitors with potent activity against multiple malaria parasite life cycle stages

Hansen, Finn K.; Sumanadasa, Subathdrage D. M.; Stenzel, Katharina; Duffy, Sandra; Meister, Stephan; Marek, Linda; Schmetter, R.; Kuna, Krystina; Hamacher, Alexandra; Mordmüller, Benjamin; Kassack, Matthias U.; Winzeler, Elizabeth A.; Avery, Vicky M.; Andrews, Katherine Thea; Kurz, Thomas

doi:10.1016/j.ejmech.2014.05.050

Cited by 69 publications

(53 citation statements)

References 44 publications

(45 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We may be able to add infections caused by protozoan parasites to this list, as genetic studies have shown that most parasite bromodomain proteins are crucial for viability and virulence. Some studies have already begun to examine the effects of bromodomain inhibitors against these protozoan parasites, and these complement previous work showing the antiparasitic activities of KAT and KDAC inhibitors (55)(56)(57)(58)(59)(60)(61)(62)(63).…”

Section: Bromodomain Inhibition In Protozoan Parasitesmentioning

confidence: 48%

Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development

Jeffers

Yang

Huang

et al. 2017

Microbiol Mol Biol Rev

View full text Add to dashboard Cite

SUMMARY Parasitic infections remain one of the most pressing global health concerns of our day, affecting billions of people and producing unsustainable economic burdens. The rise of drug-resistant parasites has created an urgent need to study their biology in hopes of uncovering new potential drug targets. It has been established that disrupting gene expression by interfering with lysine acetylation is detrimental to survival of apicomplexan (Toxoplasma gondii and Plasmodium spp.) and kinetoplastid (Leishmania spp. and Trypanosoma spp.) parasites. As “readers” of lysine acetylation, bromodomain proteins have emerged as key gene expression regulators and a promising new class of drug target. Here we review recent studies that demonstrate the essential roles played by bromodomain-containing proteins in parasite viability, invasion, and stage switching and present work showing the efficacy of bromodomain inhibitors as novel antiparasitic agents. In addition, we performed a phylogenetic analysis of bromodomain proteins in representative pathogens, some of which possess unique features that may be specific to parasite processes and useful in future drug development.

show abstract

Section: Bromodomain Inhibition In Protozoan Parasitesmentioning

confidence: 48%

Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development

Jeffers

Yang

Huang

et al. 2017

Microbiol Mol Biol Rev

View full text Add to dashboard Cite

show abstract

“…Interestingly, the N ‐hydroxy‐benzamides II are known to show decreased inhibition of human class I isoforms (Figure ) . Thus, to identify potent anti‐plasmodial HDACi with lower cytotoxicity, we designed the target compounds 1 a – k and 2 a,b by hybridizing our previously reported alkoxyamide connecting unit realized in I with a terephthalic acid‐based linker (Figure ) …”

Section: Resultsmentioning

confidence: 99%

“…Several compounds from that series revealed potent anti‐plasmodial activity against asexual blood‐stage P. falciparum parasites (IC 50 0.09–1.12 μ m ) as well as nanomolar to micromolar activity against late‐stage (IV–V) P. falciparum gametocytes ( Pf LSG IC 50 0.25–>120 μ m ) and P. berghei exo‐erythrocytic forms ( Pb EEF IC 50 0.16–7.91 μ m ). While these results suggest that it may be possible to develop HDACi that target multiple malaria parasite life cycle stages, a limitation was that the alkoxyamide‐based compounds with multi‐stage targeting activity had only moderate selectivity for parasites versus mammalian cells (SI 13–27) . With the aim of developing HDACi with improved selectivity for the parasites as well as increased potency against different Plasmodium parasite life cycle forms, herein we report the rational design, synthesis and bioactivity of a new type of anti‐plasmodial HDACi with potent activity against asexual blood‐stage parasites and exo‐erythrocytic forms.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Design and Synthesis of Terephthalic Acid‐Based Histone Deacetylase Inhibitors with Dual‐Stage Anti‐Plasmodium Activity

et al. 2017

Self Cite

View full text Add to dashboard Cite

In this work we aimed to develop parasite-selective histone deacetylase inhibitors (HDAC) inhibitors with activity against the disease-causing asexual blood stages of Plasmodium as well as causal prophylactic and/or transmission blocking properties. We report the design, synthesis, and biological testing of a series of 13 terephthalic acid-based HDAC inhibitors. All compounds showed low cytotoxicity against human embryonic kidney (HEK293) cells (IC : 8->51 μm), with 11 also having sub-micromolar in vitro activity against drug-sensitive (3D7) and multidrug-resistant (Dd2) asexual blood-stage P. falciparum parasites (IC ≈0.1-0.5 μm). A subset of compounds were examined for activity against early- and late-stage P. falciparum gametocytes and P. berghei exo-erythrocytic-stage parasites. While only moderate activity was observed against gametocytes (IC >2 μm), the most active compound (N -((3,5-dimethylbenzyl)oxy)-N -hydroxyterephthalamide, 1 f) showed sub-micromolar activity against P. berghei exo-erythrocytic stages (IC 0.18 μm) and >270-fold better activity for exo-erythrocytic forms than for HepG2 cells. This, together with asexual-stage in vitro potency (IC ≈0.1 μm) and selectivity of this compound versus human cells (SI>450), suggests that 1 f may be a valuable starting point for the development of novel antimalarial drug leads with low host cell toxicity and multi-stage anti-plasmodial activity.

show abstract

“…In particular, romidepsin was at least equipotent with the major commercial blowfly insecticides, supporting the concept of inhibiting blowfly HDAC enzymes to produce new insecticides for preventing infection by sheep blowfly, and to potentially control other insects. There is a great deal of interest currently in developing HDAC inhibitors for use in chemotherapy against other human parasitic disease – malaria, toxoplasmosis, trypanosmiasis, schistosomiasis and leishmaniasis (Andrews et al., 2012a, Andrews et al., 2012b, Andrews et al., 2014, Kelly et al., 2012, Hansen et al., 2014, Engel et al., 2015, Marek et al., 2015). A focus of these studies is the identification of HDACi that show selectivity for the parasite HDAC enzymes over the human enzymes.…”

Section: Discussionmentioning

confidence: 99%

Insecticidal activities of histone deacetylase inhibitors against a dipteran parasite of sheep, Lucilia cuprina

Bagnall

Hines

Lucke

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

View full text Add to dashboard Cite

Histone deacetylase inhibitors (HDACi) are being investigated for the control of various human parasites. Here we investigate their potential as insecticides for the control of a major ecto-parasite of sheep, the Australian sheep blowfly, Lucilia cuprina. We assessed the ability of HDACi from various chemical classes to inhibit the development of blowfly larvae in vitro, and to inhibit HDAC activity in nuclear protein extracts prepared from blowfly eggs. The HDACi prodrug romidepsin, a cyclic depsipeptide that forms a thiolate, was the most potent inhibitor of larval growth, with equivalent or greater potency than three commercial blowfly insecticides. Other HDACi with potent activity were hydroxamic acids (trichostatin, CUDC-907, AR-42), a thioester (KD5170), a disulphide (Psammaplin A), and a cyclic tetrapeptide bearing a ketone (apicidin). On the other hand, no insecticidal activity was observed for certain other hydroxamic acids, fatty acids, and the sesquiterpene lactone parthenolide. The structural diversity of the 31 hydroxamic acids examined here revealed some structural requirements for insecticidal activity; for example, among compounds with flexible linear zinc-binding extensions, greater potency was observed in the presence of branched capping groups that likely make multiple interactions with the blowfly HDAC enzymes. The insecticidal activity correlated with inhibition of HDAC activity in blowfly nuclear protein extracts, indicating that the toxicity was most likely due to inhibition of HDAC enzymes in the blowfly larvae. The inhibitor potencies against blowfly larvae are different from inhibition of human HDACs, suggesting some selectivity for human over blowfly HDACs, and a potential for developing compounds with the inverse selectivity. In summary, these novel findings support blowfly HDAC enzymes as new targets for blowfly control, and point to development of HDAC inhibitors as a promising new class of insecticides.

show abstract

Discovery of HDAC inhibitors with potent activity against multiple malaria parasite life cycle stages

Cited by 69 publications

References 44 publications

Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development

Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development

Design and Synthesis of Terephthalic Acid‐Based Histone Deacetylase Inhibitors with Dual‐Stage Anti‐Plasmodium Activity

Insecticidal activities of histone deacetylase inhibitors against a dipteran parasite of sheep, Lucilia cuprina

Contact Info

Product

Resources

About