Antileishmanial Effect of Allopurinol

Pfaller, Michael A.; Marr, J. Joseph

doi:10.1128/aac.5.5.469

Cited by 63 publications

(28 citation statements)

References 17 publications

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“…Our present results, obtained on 10 different isolates, corroborate the inhibitory activity of HPP on American Leishmania reported previously (7,15) and suggest a stronger leishmanistatic activity of APP. These latter results are similar to those found previously for T. cruzi (1) and T. rangeli (2) and for L. brasiliensis and L. donovani (9).…”

Section: Discussionsupporting

confidence: 81%

“…The capacities of several purines and pyrimidines tested to reverse the activity of HPP confirmed previously published results (7,9,15). According to earlier reports, adenine at 10 times the concentration of HPP did not prevent entry of HPP, but blocked its conversion to nucleoside.…”

Section: Discussionsupporting

confidence: 77%

“…Since the two pyrazolopyrimidines allopurinol (4-hydroxypyrazolo[3,4-dJpyrimidine; HPP) and allopurinol riboside (HPPR) have been shown to be effective in vitro against both American Leishmania species (11,15), the effects of 4-aminopyrazolopyrimidine (APP) and APP-2'-deoxyriboside on these species were studied. We have already shown that Trypanosoma cruzi (1) and Trypanosoma rangeli (2) are susceptible to these agents.…”

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confidence: 99%

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Comparative effects of 4-aminopyrazolopyrimidine, its 2'-deoxyriboside derivative, and allopurinol on in vitro growth of American Leishmania species

Avila¹,

Casanova²

1982

Antimicrob Agents Chemother

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When assayed on promastigotes of 10 American Leishmania isolates (including Leishmania brasiliensis and mexicana species), 4-aminopyrazolopyrimidine (APP) was severalfold more active than allopurinol as a leishmanistatic drug. There were some intraspecific and interspecific differences among the isolates in their susceptibility to the inhibitory effects of APP and allopurinol. APP-2'-deoxyriboside did not affect the 10 isolates tested. This was surprising, because allopurinol riboside has previously been shown to be more active than allopurinol.In all of the American Leishmania isolates tested, the metabolism of [14C]6-APP resulted in a high level of HPP-ribose-5'-P and lower levels of APP-ribose-5'-P, APP-ribose-5'-PP, and APP-ribose-5'-PPP. MP, LR, LBY, and JAP isolates strongly converted APP into APP derivatives, thus perhaps explaining their greater susceptibility to the inhibitory effects of APP. With the 10 American Leishmania isolates tested, several purines reversed the inhibitory effects of allopurinol, but only adenine countered the inhibitory effects of APP. This suggests biochemical differences in the mechanisms of action of allopurinol and APP. Finally, and contrary to previous claims, the reversal by purines of the allopurinol-induced growth inhibition was not a Leishmania species-specific effect.In South and Central America, cutaneous and mucocutaneous leishmaniasis are caused by Leishmania mexicana or Leishmania brasiliensis infection (6). Since the two pyrazolopyrimidines allopurinol (4-hydroxypyrazolo[3,4-dJpyrimidine; HPP) and allopurinol riboside (HPPR) have been shown to be effective in vitro against both American Leishmania species (11,15), the effects of 4-aminopyrazolopyrimidine (APP) and APP-2'-deoxyriboside on these species were studied. We have already shown that Trypanosoma cruzi (1) and Trypanosoma rangeli (2) are susceptible to these agents.This study compares the antileishmanial activity of APP, APP-2'-deoxyriboside, and HPP on promastigotes of 10 American Leishmania isolates, reversal of the activities of APP and HPP by different purines and pyrimidines, and the metabolism of [14C]APP for each isolate.MATERIALS AND METHODS Culture methods. American Leishmania isolates were grown at 28°C in a semidefined fetal calf serumcontaining medium (3). L. mexicana isolates (AMP, AZV, and LR isolates) were obtained from W. Torrealba, Valencia, Venezuela (13,14), and J. Convit, Caracas, Venezuela. L. mexicana pifanoi (MP isolate) and amazonensis (M1132; MA isolate) subspecies were supplied by R. Lainson, Belem, Brasil (4). L. brasiliensis (NR isolate) was obtained from J. Convit (5). L. brasiliensis guyanensis (H1; BG isolate) and yaracuyensis (LBY isolate) subspecies were supplied by R. Lainson (4) and F. Pifano, Caracas, Venezuela, respectively. L. garnhami (JAP and HM isolates) were obtained from J. V. Scorza, Merida, Venezuela (18). Promastigotes were cultured in 30-ml plastic tissue culture flasks (Fisher Scientific Co., Springfield, N.J.), using an inoculum of 0.5 x 106 parasites p...

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 77%

mentioning

confidence: 99%

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Comparative effects of 4-aminopyrazolopyrimidine, its 2'-deoxyriboside derivative, and allopurinol on in vitro growth of American Leishmania species

Avila¹,

Casanova²

1982

Antimicrob Agents Chemother

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“…A second rationale was that Leishmania are purine auxotrophs, with highly active and multiply redundant pathways for uptake and activation of nucleobases and nucleosides (31). Indeed, a great deal of prior effort has been devoted to the development of antileishmanial purine analogs; however, whereas the nucleobase allopurinol is commonly used as a veterinary agent, it has proven more difficult to find agents of sufficient potency and selectivity against Leishmania to be used widely against human leishmaniasis (32). We reasoned that the highly divergent properties of Totiviridae RDRPs, relative to the polymerases of both the Leishmania and mammalian hosts (as well as other viral RDRPs), could prove fertile grounds for antiviral discovery, especially when coupled with potentiation by the parasite's powerful nucleoside/base salvage pathways.…”

Section: Significancementioning

confidence: 99%

Antiviral screening identifies adenosine analogs targeting the endogenous dsRNALeishmaniaRNA virus 1 (LRV1) pathogenicity factor

Kuhlmann

Robinson

Bluemling

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The endogenous double-stranded RNA (dsRNA) virus Leishmaniavirus (LRV1) has been implicated as a pathogenicity factor for leishmaniasis in rodent models and human disease, and associated with drug-treatment failures in Leishmania braziliensis and Leishmania guyanensis infections. Thus, methods targeting LRV1 could have therapeutic benefit. Here we screened a panel of antivirals for parasite and LRV1 inhibition, focusing on nucleoside analogs to capitalize on the highly active salvage pathways of Leishmania, which are purine auxotrophs. Applying a capsid flow cytometry assay, we identified two 2′-C-methyladenosine analogs showing selective inhibition of LRV1. Treatment resulted in loss of LRV1 with first-order kinetics, as expected for random virus segregation, and elimination within six cell doublings, consistent with a measured LRV1 copy number of about 15. Viral loss was specific to antiviral nucleoside treatment and not induced by growth inhibitors, in contrast to fungal dsRNA viruses. Comparisons of drug-treated LRV1 + and LRV1 − lines recapitulated LRV1-dependent pathology and parasite replication in mouse infections, and cytokine secretion in macrophage infections. Agents targeting Totiviridae have not been described previously, nor are there many examples of inhibitors acting against dsRNA viruses more generally. The compounds identified here provide a key proof-ofprinciple in support of further studies identifying efficacious antivirals for use in in vivo studies of LRV1-mediated virulence.trypanosomatid protozoan parasite | endobiont virus | viral segregation | chemotherapy | virulence

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“…Current evidence indicates that purine analogues alone or in combination with other chemotherapeutic agents are very effective against almost any fast-growing cells (22,41). Allopurinol, a purine analogue, has been used to treat leishmaniasis alone (34,48) or combined with other drugs (21,35,36,39,47). It should be pointed out, however, that the efficacy of allopurinol monotherapy remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Purine Nucleobase Transport in Amastigotes of Leishmania mexicana : Involvement in Allopurinol Uptake

Al-Salabi

Koning

2005

Antimicrob Agents Chemother

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Nucleobase and nucleoside transporters play central roles in the biochemistry of parasitic protozoa, as they lack the ability to synthesize purines de novo and are absolutely reliant upon purine salvage from their hosts. Furthermore, such transporters are potentially critical to the pharmacology of these important human pathogens, because they mediate the uptake of purine analogues, as well as some nonpurine drugs, that can be selectively cytotoxic to the parasites. We here report the first identification and characterization of a purine nucleobase transporter in Leishmania amastigotes. Uptake of [ 3 H]hypoxanthine by Leishmania mexicana amastigotes was mediated by a single high-affinity transporter, LmexNBT1, with a K m of 1.6 ؎ 0.4 M and high affinity for adenine, guanine, and xanthine but low affinity for nucleosides and pyrimidine nucleobases. Allopurinol, an antileishmanial hypoxanthine analogue, was apparently taken up by the same transporter. Using Parasitic protozoa of the genus Leishmania are the etiological agents of leishmaniasis. Some 12 million people throughout the world suffer from leishmaniasis, ranging from the disfiguring cutaneous form to often-fatal visceral leishmaniasis. Leishmania species are sandfly-transmitted protozoan parasites. The life cycle is divided into promastigotes and metacyclics in the insect vectors and amastigotes in their mammalian hosts, which are responsible for all clinical manifestations.Most of the currently available antileishmanial drugs have been discovered empirically, as until recently insufficient information was known about the biochemistry, physiology, and molecular biology of these parasites and the interactions with their hosts (23). The limitations of the current treatment for leishmaniasis, as a result of drug resistance and the severe side effects of most of the existing therapeutic agents, and the urgent need for new therapeutic approaches, are well documented (12,56,60).The development of a rational therapeutic strategy for the treatment and prevention of parasitic disease depends on exploitation of fundamental biochemical disparities between parasite and host, such as the inability of protozoan parasites to synthesize purines de novo (5). Current antiprotozoal agents often derive selectivity from selective accumulation by the parasite rather than the host cell (15). The selectivity and the efficacy of purine antimetabolites can be achieved by the cell surface transporters that mediate access to the cell, as substrate recognition by nucleobase transporters is strikingly different in humans and kinetoplastids such as Trypanosoma brucei (58) and Leishmania major promastigotes (2). Purine and pyrimidine antimetabolites have been highly successful against many viral infections as well as malignancies (27) and show great promise against protozoal infections as well (reviewed in references 14, 17, and 23). Allopurinol, a purine nucleobase analogue, is clinically used against various manifestations of leishmaniasis (1,13,39).Whereas purine transporters in prom...

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Antileishmanial Effect of Allopurinol

Cited by 63 publications

References 17 publications

Comparative effects of 4-aminopyrazolopyrimidine, its 2'-deoxyriboside derivative, and allopurinol on in vitro growth of American Leishmania species

Comparative effects of 4-aminopyrazolopyrimidine, its 2'-deoxyriboside derivative, and allopurinol on in vitro growth of American Leishmania species

Antiviral screening identifies adenosine analogs targeting the endogenous dsRNALeishmaniaRNA virus 1 (LRV1) pathogenicity factor

Purine Nucleobase Transport in Amastigotes of Leishmania mexicana : Involvement in Allopurinol Uptake

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