Analogs of pentamidine as potential anti-Pneumocystis chemotherapeutics

Maciejewska, Dorota; Żabiński, Jerzy; Kaźmierczak, Paweł; Rezler, Mateusz; Krassowska‐Swiebocka, Barbara; Collins, Margaret S.; Cushion, Melanie T.

doi:10.1016/j.ejmech.2011.12.010

Cited by 18 publications

(32 citation statements)

References 27 publications

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“…ATP was measured using a bioluminescence assay as previously described (48). The linear range of the ATP assay is 1 μM to 100 fM (~20,000,000 to 2,000 RLU).…”

Section: Methodsmentioning

confidence: 99%

Functional Characterization of Pneumocystis carinii Inositol Transporter 1

Cushion

Collins

Sesterhenn

et al. 2016

mBio

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Fungi in the genus Pneumocystis live in the lungs of mammals, where they can cause a fatal pneumonia (PCP [Pneumocystis pneumonia]) in hosts with compromised immune systems. The absence of a continuous in vitro culture system for any species of Pneumocystis has led to limited understanding of these fungi, especially for the discovery of new therapies. We recently reported that Pneumocystis carinii, Pneumocystis murina, and most significantly, Pneumocystis jirovecii lack both enzymes necessary for myo-inositol biosynthesis but contain genes with homologies to fungal myo-inositol transporters. Since myo-inositol is essential for eukaryotic viability, the primary transporter, ITR1, was functionally and structurally characterized in P. carinii. The predicted structure of P. carinii ITR1 (PcITR1) contained 12 transmembrane alpha-helices with intracellular C and N termini, consistent with other inositol transporters. The apparent Km was 0.94 ± 0.08 (mean ± standard deviation), suggesting that myo-inositol transport in P. carinii is likely through a low-affinity, highly selective transport system, as no other sugars or inositol stereoisomers were significant competitive inhibitors. Glucose transport was shown to use a different transport system. The myo-inositol transport was distinct from mammalian transporters, as it was not sodium dependent and was cytochalasin B resistant. Inositol transport in these fungi offers an attractive new drug target because of the reliance of the fungi on its transport, clear differences between the mammalian and fungal transporters, and the ability of the host to both synthesize and transport this critical nutrient, predicting low toxicity of potential inhibitors to the fungal transporter.

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“…ATP was measured using a bioluminescence assay as previously described (48). The linear range of the ATP assay is 1 μM to 100 fM (~20,000,000 to 2,000 RLU).…”

Section: Methodsmentioning

confidence: 99%

Functional Characterization of Pneumocystis carinii Inositol Transporter 1

Cushion

Collins

Sesterhenn

et al. 2016

mBio

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“…The medium was removed and replaced with fresh medium containing controls and test compound at appropriate dilutions. Assays of three time points (24,48, and 72 h) with triplicate wells were sampled. The medium was aspirated from the wells.…”

Section: (Ii) Synthesismentioning

confidence: 99%

Chloroquine Analogues as Leads against Pneumocystis Lung Pathogens

Gomes

Ferraz

Ficker³

et al. 2018

Antimicrob Agents Chemother

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The impact of pneumonia (PcP) on morbidity and mortality remains substantial for immunocompromised individuals, including those afflicted by HIV infection, organ transplantation, cancer, autoimmune diseases, or subject to chemotherapy or corticosteroid-based therapies. Previous work from our group has shown that repurposing antimalarial compounds for PcP holds promise for treatment of this opportunistic infection. Following our previous discovery of chloroquine analogues with dual-stage antimalarial action both and , we now report the potent action of these compounds on Identification of chloroquine analogues as anti-PcP leads is an unprecedented finding.

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“…More recently, a series of 20 pentamidine analogues (106) were prepared using the general (Scheme 32) that evaluated heteroatoms, sulfobenzene and alkanediamide groups in the aliphatic linker and methoxy substituents attached to the benzene rings for efficacy against the fungal pathogen, Pneumocystis carinii in an ATP bioassay [79]. All but one of the 20 bisamidines prepared reduced the ATP content of the P. carinii over the 72 h of the assay period.…”

Section: Cnmentioning

confidence: 99%

New Pentamidine Analogues in Medicinal Chemistry

Porcheddu¹,

Giacomelli²,

Luca³

2012

CMC

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Sixty years after its introduction, 1,5-bis(4-amidinophenoxy)pentane (Pentamidine) is still one of the most used drugs for the treatment of the first stage of Human African trypanosomiasis and other neglected diseases such as malaria and leishmaniasis. These protozoan infections are prevalent in the poorest world areas such as sub-saharian and developing countries, however the increasing immigration from these countries to the richest part of the world and the overlap of HIV with parasitic infections result in a growing number of cases in developed nations. A great effort has been made to develop new generations of diamidines for the treatment of these infections transmitted by insects. This review summarises the synthesis and evaluation of pentamidine analogues reported in the last years in the effort to find new drugs with better pharmaceutical activity, higher lipophilicity and lower citotoxycicty.

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Analogs of pentamidine as potential anti-Pneumocystis chemotherapeutics

Cited by 18 publications

References 27 publications

Functional Characterization of Pneumocystis carinii Inositol Transporter 1

Functional Characterization of Pneumocystis carinii Inositol Transporter 1

Chloroquine Analogues as Leads against Pneumocystis Lung Pathogens

New Pentamidine Analogues in Medicinal Chemistry

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