Lead Optimization of Imidazopyrazines: A New Class of Antimalarial with Activity on <i>Plasmodium</i> Liver Stages

Zou, Bin; Nagle, A. S.; Chatterjee, Arnab K.; Leong, Seh Yong; Tan, Liying Jocelyn; Sim, Wei Lin Sandra; Mishra, Prateek; Guntapalli, Prasuna; Tully, David C.; Lakshminarayana, Suresh B.; Lim, Chek Shik; Tan, Yong; Abas, Siti Nurdiana; Bodenreider, Christophe; Kuhen, Kelli; Gagaring, Kerstin; Borboa, Rachel; Chang, Jonathan; Li, Chun; Hollenbeck, Thomas; Tuntland, Tove; Zeeman, Anne‐Marie; Kocken, Clemens H. M.; McNamara, Case W.; Kato, Nobutaka; Winzeler, Elizabeth A.; Yeung, Bryan K. S.; Diagana, Thierry T.; Smith, Paul W.; Roland, Jason

doi:10.1021/ml500244m

Cited by 32 publications

(29 citation statements)

References 12 publications

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“…Notably, many anti-malarials (spiroindolones9, cyclomarins10 and imidazolopiperazines11) lacked activity against Cryptosporidium , however 154 compounds showed >60% growth inhibition at 5 μM. Secondary screening using a novel cytopathic effect (CPE) based C. parvum assay confirmed several scaffolds, with imidazopyrazines12,13 and pyrazolopyridines14 showing sub-micromolar cellular activity (Fig. 1a-d and Table 1, structures provided in Extended Data Fig.1).…”

Section: Cryptosporidium Compound Screenmentioning

confidence: 94%

A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis

Manjunatha¹,

Vinayak

Zambriski

et al. 2017

Nature

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168

142

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Diarrheal disease is responsible for 8.6% of global child mortality. Recent epidemiological studies found the protozoan parasite Cryptosporidium to be a leading cause of pediatric diarrhea with particularly grave impact on infants and immunocompromised individuals. There is neither a vaccine nor effective treatment. We establish a drug discovery process built on scalable phenotypic assays and mouse models that takes advantage of transgenic parasites. Screening a library of compounds with anti-parasitic activity we identified pyrazolopyridines as inhibitors of Cryptosporidium parvum and C. hominis. Oral treatment with the pyrazolopyridine KDU731 results in potent reduction in intestinal infection of immunocompromised mice. Treatment also leads to rapid resolution of diarrhea and dehydration in neonatal calves, a clinical model of cryptosporidiosis that closely resembles human infection. Our results suggest the Cryptosporidium lipid kinase PI(4)K as a target for pyrazolopyridines and warrant further preclinical evaluation of KDU731 as a drug candidate for the treatment of cryptosporidiosis.

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Section: Cryptosporidium Compound Screenmentioning

confidence: 94%

A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis

Manjunatha¹,

Vinayak

Zambriski

et al. 2017

Nature

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168

142

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“…How effective is primaquine for killing putative extrahepatic and nonbloodstream, latent P. vivax and P. ovale parasites? Compounds that eliminate presumed hypnozoites are being identified [84][85][86][87][88]. However, are the singly occurring, hypnozoitelike parasites that can be inactivated in vitro responsible for malarial recurrences in vivo?…”

Section: Box 3 Outstanding Questions and Research Directions (Also Smentioning

confidence: 99%

Do hypnozoites cause relapse in malaria?

Markus

2015

Trends in Parasitology

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“…The target of KAI407 was later determined to be Plasmodium PI4 kinase (PI4K) ( 11 ), and we hypothesized that compounds that are active against this target may also possess antihypnozoite activity in vivo similar that of PQ. We have since identified other analogues, KDU691 ( 12 ) and LMV599 (our unpublished data), which have improved potency on P. cynomolgi liver stages and better drug-like properties than KAI407. We present the in vivo efficacy profiles of these inhibitors when orally administered as causal prophylaxis or radical-cure agents in P. cynomolgi sporozoite-infected rhesus monkeys.…”

Section: Introductionmentioning

confidence: 99%

PI4 Kinase Is a Prophylactic but Not Radical Curative Target in Plasmodium vivax-Type Malaria Parasites

Zeeman

Lakshminarayana

Werff

et al. 2016

Antimicrob Agents Chemother

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Two Plasmodium PI4 kinase (PI4K) inhibitors, KDU691 and LMV599, were selected for in vivo testing as causal prophylactic and radical-cure agents for Plasmodium cynomolgi sporozoite-infected rhesus macaques, based on their in vitro activity against liver stages. Animals were infected with P. cynomolgi sporozoites, and compounds were dosed orally. Both the KDU691 and LMV599 compounds were fully protective when administered prophylactically, and the more potent compound LMV599 achieved protection as a single oral dose of 25 mg/kg of body weight. In contrast, when tested for radical cure, five daily doses of 20 mg/kg of KDU691 or 25 mg/kg of LMV599 did not prevent relapse, as all animals experienced a secondary infection due to the reactivation of hypnozoites in the liver. Pharmacokinetic data show that LMV599 achieved plasma exposure that was sufficient to achieve efficacy based on our in vitro data. These findings indicate that Plasmodium PI4K is a potential drug target for malaria prophylaxis but not radical cure. Longer in vitro culture systems will be required to assess these compounds' activity on established hypnozoites and predict radical cure in vivo.

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Lead Optimization of Imidazopyrazines: A New Class of Antimalarial with Activity on Plasmodium Liver Stages

Cited by 32 publications

References 12 publications

A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis

A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis

Do hypnozoites cause relapse in malaria?

PI4 Kinase Is a Prophylactic but Not Radical Curative Target in Plasmodium vivax-Type Malaria Parasites

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