Phthalazinone inhibitors of inosine-5′-monophosphate dehydrogenase from Cryptosporidium parvum

Johnson, Corey R.; Gorla, Suresh Kumar; Mandapati, Kavitha; Zhang, Minjia; Liu, Xiaoping; Striepen, Boris; Mead, Jan R.; Cuny, Gregory D.; Hedstrom, Lizbeth

doi:10.1016/j.bmcl.2012.12.037

Cited by 44 publications

(42 citation statements)

References 18 publications

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“…In as much as they, harbor a wide variety of parasites which can be detrimental to their and human health (Calvete et al 1998;Hille et al 2014;Krecek et al 2010;Ramos et al 2013;Scorza et al 2011;Silaghi et al 2014), and also represent potential reservoirs of helminthic parasites to domestic cats and human, especially in urban areas (Hille et al 2014;Polak et al 2014;Youssef and Uga 2014). Besides, due to their contact with both domestic cats and humans, stray cat may play an important role in the transmission of several pathogenic agents; such as Toxoplasma gondii (Can et al 2014;Lappin 2010;Vilares et al 2014) and Cryptosporidium (Bush et al 2011;Scorza et al 2011;Spada et al 2013;Spain et al 2001) that have the ability to cause life-threatening infections in individuals (Davoust et al 2014;Johnson et al 2013), or Leishmania infantum (Chatzis et al 2014;Hatam et al 2010;Pennisi et al 2013;Richter et al 2014) and Toxocara spp. which have been associated with two main clinical syndromes in humans (ocular larva migrans and visceral larva migrans) (Bowman et al 2010;Fisher 2003;Petithory 2007;Prokopowicz and Sosnowska 1990;Rubinsky-Elefant et al 2010).…”

Section: Introductionmentioning

confidence: 99%

A survey study on gastrointestinal parasites of stray cats in Azarshahr, (East Azerbaijan province, Iran)

et al. 2015

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Gastrointestinal parasites are among the most common parasitic infections found in stray cats, which might act potential helminthic parasites to domestic cats. The objective of this study was to determine the prevalence of gastrointestinal parasites in stray cats in the city of Azarshahr, which is located in East Azerbaijan province, Iran. A cross-sectional study was conducted on 50 necropsied stray cats, trapped and collected from different geographic regions of Azarshahr. From a total 50 stray cats examined, 15 (30 %) were female and 35 (70 %) were male. Overall 47 cats (94 %) were identified as infected with at least one of the endoparasites. The prevalence of parasites found were: Taenia taeniaeformis (60 %), Dipylidium caninum (58 %), Taenia hydatigera (24 %), Mesocestoides lineatus (78 %), Ancylostoma tubaeforme (14 %), Toxascaris leonina (30 %), Toxocara cati (78 %), Physaloptera praeputialis (10 %), and Syphacia obvelata (10 %). Contamination rate for zoonotic parasites of cat was greater than expected in AzarShahr region. Therefore, appropriate control measures should be taken and preventive methods should be applied.

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Section: Introductionmentioning

confidence: 99%

A survey study on gastrointestinal parasites of stray cats in Azarshahr, (East Azerbaijan province, Iran)

et al. 2015

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“…Thus, the exclusive reliance on the salvage pathway by Cryptosporidium and its high metabolic demand for nucleotides due to the parasite's complicated lifecycle make IMPDH a potential drug target candidate. This hypothesis is supported by the recent discovery of several Cryptosporidium IMPDH inhibitors Johnson et al, 2013;Maurya et al, 2009;Sharling et al, 2010;Umejiego et al, 2008).…”

Section: Introductionmentioning

confidence: 80%

“…Despite this, efforts to develop new and more effective treatments for this disease have been hindered by (1) lack of suitable targets and (2) lack of target validation and transfection tools. The completion of the Cryptosporidium genome (Abrahamsen et al, 2004;Xu et al, 2004), which resulted in a range of potential drug targets being identified, has overcome the first hindrance and IMPDH is now a well recognised and important drug target Johnson et al, 2013;Maurya et al, 2009;Sharling et al, 2010;Umejiego et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Target validation of the inosine monophosphate dehydrogenase (IMPDH) gene in Cryptosporidium using Phylomer® peptides

Jefferies

Yang

Woh

et al. 2015

Experimental Parasitology

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• Yielded a relatively high functional hit rate (~17% i.e. 2/12 Phylomer ® peptides tested).• Successfully shown that TAT can deliver therapeutic Phylomer cargoes inside cells.• Opens up new therapeutic opportunities. Cryptosporidiosis, a gastroenteric disease characterised mainly by diarrheal illnesses in humans and mammals is caused by infection with the protozoan parasite Cryptosporidium. Treatment options for cryptosporidiosis are limited, with the current therapeutic nitazoxanide, only partly efficacious in immunocompetent individuals. The parasite lacks de novo purine synthesis, and is exclusively dependant on purine salvage from its host. Inhibition of the inosine 5' monophosphate dehydrogenase (IMPDH), a purine salvage enzyme that is essential for DNA synthesis, thereby offers a potential drug target against this parasite. In the present study, a yeast-two-hybrid system was used to identify Phylomer peptides within a library constructed from the genomes of 25 phylogenetically diverse bacteria that targeted the IMPDH of Cryptosporidium parvum (IMPcp) and Cryptosporidium hominis (IMPch). We identified 38 unique interacting Phylomers, of which, 12 were synthesised and screened against C. parvum in vitro. Two Phylomers exhibited significant growth inhibition (81.2-83.8% inhibition; P < 0.05), one of which consistently 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 exhibited positive interactions with IMPcp and IMPch during primary and recapitulation yeast two-hybrid screening and did not interact with either of the human IMPDH proteins. The present study highlightsthe potential of Phylomer peptides as target validation tools for Cryptosporidium and other organisms and diseases because of their ability to bind with high affinity to target proteins and disrupt function. G R A P H I C A L A B S T R A C T

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“…Moreover, the CpIMPDH gene was obtained from an epsilonproteobacterium by lateral gene transfer and thus is very different from host IMPDHs (30,43). We have developed several structurally distinct classes of CpIMPDH inhibitors, achieving nanomolar potency and selectivity in excess of 1,000-fold versus the human enzymes (44)(45)(46)(47)(48)(49)(50). Here, we report the antiparasitic activity of our eight most promising compounds in the interleukin-12 (IL-12) knockout mouse model.…”

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confidence: 99%

Validation of IMP Dehydrogenase Inhibitors in a Mouse Model of Cryptosporidiosis

Gorla

McNair

Yang

et al. 2014

Antimicrob Agents Chemother

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f Cryptosporidium parasites are a major cause of diarrhea and malnutrition in the developing world, a frequent cause of waterborne disease in the developed world, and a potential bioterrorism agent. Currently, available treatment is limited, and Cryptosporidium drug discovery remains largely unsuccessful. As a result, the pharmacokinetic properties required for in vivo efficacy have not been established. We have been engaged in a Cryptosporidium drug discovery program targeting IMP dehydrogenase (CpIMPDH). Here, we report the activity of eight potent and selective inhibitors of CpIMPDH in the interleukin-12 (IL-12) knockout mouse model, which mimics acute human cryptosporidiosis. Two compounds displayed significant antiparasitic activity, validating CpIMPDH as a drug target. The best compound, P131 (250 mg/kg of body weight/day), performed equivalently to paromomycin (2,000 mg/kg/day) when administered in a single dose and better than paromomycin when administered in three daily doses. One compound, A110, appeared to promote Cryptosporidium infection. The pharmacokinetic, uptake, and permeability properties of the eight compounds were measured. P131 had the lowest systemic distribution but accumulated to high concentrations within intestinal cells. A110 had the highest systemic distribution. These observations suggest that systemic distribution is not required, and may be a liability, for in vivo antiparasitic activity. Intriguingly, A110 caused specific alterations in fecal microbiota that were not observed with P131 or vehicle alone. Such changes may explain how A110 promotes parasitemia. Collectively, these observations suggest a blueprint for the development of anticryptosporidial therapy.

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Phthalazinone inhibitors of inosine-5′-monophosphate dehydrogenase from Cryptosporidium parvum

Cited by 44 publications

References 18 publications

A survey study on gastrointestinal parasites of stray cats in Azarshahr, (East Azerbaijan province, Iran)

A survey study on gastrointestinal parasites of stray cats in Azarshahr, (East Azerbaijan province, Iran)

Target validation of the inosine monophosphate dehydrogenase (IMPDH) gene in Cryptosporidium using Phylomer® peptides

Validation of IMP Dehydrogenase Inhibitors in a Mouse Model of Cryptosporidiosis

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