Novel molecular targets for antimalarial chemotherapy

Jana, Snehasis; Paliwal, Jyoti

doi:10.1016/j.ijantimicag.2007.01.002

Cited by 59 publications

(48 citation statements)

References 49 publications

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“…Since the unveiling of the P. falciparum genome in 2002 [24], a number of potential targets for drug intervention have emerged [19,43,44] (Table 1). These potential antimalarial drug targets can be broadly classified into three categories, according to their function in the parasite's life cycle [25,45]: i) targets involved in macromolecular and metabolite synthesis, ii) targets engaged in membrane transport and signaling, and iii) targets involved in hemoglobin degradation.…”

Section: Antimalarial Therapymentioning

confidence: 99%

Falcipains, Plasmodium falciparum Cysteine Proteases as Key Drug Targets Against Malaria

Teixeira¹,

Gomes²,

Gomes

2011

CMC

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There is a high demand for new drugs against malaria, which takes millions of lives annually. The abuse of classical antimalarials from the late 1940's to the early 1980's has bred resistant parasites, which led to the use of more potent drugs that ended up by refueling the resistance cycle. An example is chloroquine, once highly effective but now virtually useless against malaria.Structure-based rational drug design relies on high-resolution target structures to allow for screening of selective ligands/inhibitors. For the past two decades, and especially after the unveiling of the Plasmodium falciparum genome in 2002, enzymes of this lethal malaria parasite species have been increasingly attracting the attention of Medicinal Chemists worldwide as promising drug targets. There is particular emphasis on proteases having key roles on the degradation of host's hemoglobin within the food vacuole of blood-stage parasites, as these depend on such process for their survival. Among such enzymes, Plasmepsins (aspartic proteases) and, especially, Falcipains (cysteine proteases) are highly promising antimalarial drug targets. The present review will focus on the computational approaches made so far towards the unraveling of the structure, function and inhibition of Falcipains that, by virtue of their quite specific features, are excellent targets for highly selective inhibitors.

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Section: Antimalarial Therapymentioning

confidence: 99%

Falcipains, Plasmodium falciparum Cysteine Proteases as Key Drug Targets Against Malaria

Teixeira¹,

Gomes²,

Gomes

2011

CMC

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“…In this regard, biochemical pathways general to parasites but absent from mammalian hosts have long been an attractive source of molecular targets for anti-infective drug development [23,27]. Additionally, biochemical peculiarities of the parasites such as (i) turnover rates [42,43]; (ii) structure of biological membranes [44][45][46][47]; (iii) cell signaling [48] and (iv) protein expression and regulation [49] have also been investigated as potential targets for drug intervention [50].…”

Section: Molecular Targets For Drug Designmentioning

confidence: 99%

Structure-Based Drug Discovery for Tropical Diseases

Güido

Oliva

2009

CTMC

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Parasitic diseases are amongst the foremost threats to human health and welfare around the world. In tropical and subtropical regions of the world, the consequences of parasitic infections are devastating both in terms of human morbidity and mortality. The current available drugs are limited, ineffective, and require long treatment regimens. To overcome these limitations, the identification of new macromolecular targets and small-molecule modulators is of utmost importance. The advances in genomics and proteomics have prompted drug discovery to move toward more rational strategies. The increasing understanding of the fundamental principles of protein-ligand interactions combined with the availability of compound libraries has facilitated the identification of promising hits and the generation of high quality lead compounds for tropical diseases. This review presents the current progresses and applications of structure-based drug design (SBDD) for the discovery of innovative chemotherapy agents for a variety of parasitic diseases, highlighting the challenges, limitations, and future perspectives in medicinal chemistry.

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“…9 Under the present scenario, the development of resistance by the parasite against first-and second-line antimalarial drugs is proving to be a challenging problem in malaria control in most parts of the world as no licensed vaccine exists yet. 10,11 During the later 1940s and the 1950s, the 4-aminoquinoline chloroquine (CQ) proved invaluable worldwide as a safe and cheap suppressive prophylactic and as a therapeutic antimalarial. Since the early 60s, the sensitivity of the parasites to CQ has been on a gradual decline.…”

Section: Introductionmentioning

confidence: 99%

Falcipain‐2 inhibitors

Ettari

Bova

Zappalà

et al. 2009

Medicinal Research Reviews

131

106

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Malaria, particularly that one caused by Plasmodium falciparum, remains a serious health problem in Africa, South America, and many parts of Asia where it afflicts about 500 million people and is responsible for the death of more than one million children each year. The main reasons for the persistence of malaria are the emergence of resistance to common antimalarial drugs, inadequate control of mosquito vectors, and the lack of effective vaccines. Therefore, the identification and characterization of new targets for antimalarial chemotherapy are of urgent priority. This review is focused on inhibitors of falcipain-2, a cysteine protease from P. falciparum, which represents one of the most promising targets for antimalarial drug design. Falcipain-2 is a key enzyme in the life cycle of P. falciparum since it degrades hemoglobin, at the early trophozoite stage, and cleaves ankyrin and protein 4.1, the cytoskeletal elements vital to the stability of red cell membrane, at the schizont stage. The main classes of falcipain-2 inhibitors are peptides or peptidomimetics bearing the most popular pharmacophores of cysteine protease inhibitors, such as vinyl sulfones, halomethyl ketones, and aldehydes. Furthermore, many other chemotypes have been identified as inhibitors of falcipain-2, such as isoquinolines, thiosemicarbazones, and chalcones. These inhibitors represent all classes, which, to the best of our knowledge, have been disclosed in journal articles to date.

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Novel molecular targets for antimalarial chemotherapy

Cited by 59 publications

References 49 publications

Falcipains, Plasmodium falciparum Cysteine Proteases as Key Drug Targets Against Malaria

Falcipains, Plasmodium falciparum Cysteine Proteases as Key Drug Targets Against Malaria

Structure-Based Drug Discovery for Tropical Diseases

Falcipain‐2 inhibitors

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