Global Phenotypic Screening for Antimalarials

Guiguemde, W. Armand; Shelat, Anang A.; Garcia-Bustos, José; Diagana, Thierry T.; Gamo, Francisco‐Javier; Guy, R. Kiplin

doi:10.1016/j.chembiol.2012.01.004

“…Since the 1980s and until the mid-2000s the development of new antimalarials was carried out trying to modify existing chemotypes or to assess the validity of new targets identified through genetic and/or in silico insights [26]. However, these strategies did not lead to the deployment of new antimalarials, and have been generally recognized as unsatisfactory because of the small number of available scaffolds, for the lack of whole-cell activity, and/or for the rapid in vitro development of resistance [23,26]. Therefore, to identify novel antimalarial leads major pharmaceutical firms and academic institutions chose to screen large chemical libraries using high throughput, whole cell screening assays based on P. falciparum proliferation.…”

Section: New Approachesmentioning

confidence: 99%

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

Zucca¹,

Scutera²,

Savoia³

2013

Current Medicinal Chemistry

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Due to the persistent lack of suitable vaccines, chemotherapy remains the only option for the treatment of patients infected by protozoan parasites. However, most available antiparasitic drugs have serious disadvantages, ranging from high cost and poor compliance to high toxicity and rapid induction of resistance. In recent decades basic research laboratories identified a considerable number of promising new molecules, but their development has not been pursued in depth by pharmaceutical firms because of poor prospects of economic return. The establishment of adequately funded public-private partnerships is currently reversing the trend. This review deals with new drugs against Plasmodium, Leishmania and Trypanosoma parasites, focusing on the molecules that are in the most advanced stage of development. The purpose of this article is to provide the reader with a panoramic view of the updated literature on the challenges and strategies of contemporary antiprotozoal drug research, paying the due attention to the already published reviews.

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“…MK-4815 is undergoing further evaluation and was accepted as a preclinical candidate by the MMV [104]. High priority molecules in the lead optimization, preclinical or phase I development stage are thoroughly reviewed in [26].…”

Section: New Approachesmentioning

confidence: 99%

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

Zucca

¹

,

Scutera²,

Savoia³

2013

CMC

View full text Add to dashboard Cite

Due to the persistent lack of suitable vaccines, chemotherapy remains the only option for the treatment of patients infected by protozoan parasites. However, most available antiparasitic drugs have serious disadvantages, ranging from high cost and poor compliance to high toxicity and rapid induction of resistance. In recent decades basic research laboratories identified a considerable number of promising new molecules, but their development has not been pursued in depth by pharmaceutical firms because of poor prospects of economic return. The establishment of adequately funded public-private partnerships is currently reversing the trend. This review deals with new drugs against Plasmodium, Leishmania and Trypanosoma parasites, focusing on the molecules that are in the most advanced stage of development. The purpose of this article is to provide the reader with a panoramic view of the updated literature on the challenges and strategies of contemporary antiprotozoal drug research, paying the due attention to the already published reviews.Keywords: Antibiotics, antiprotozoal chemotherapy, Leishmania, natural products, Plasmodium, Trypanosoma. 4 INTRODUCTIONInfections caused by parasitic protozoa take an enormous toll on human health. Their prevalence is higher in tropical and equatorial countries, where the major number of deaths is due to malaria, leishmaniasis, and African and American trypanosomiasis. High mortality rates are associated to poor sanitary conditions, high percentages of untreated HIV-infected individuals, and lack of efficient prophylactic measures [1]. In the developed countries the situation is not so tragic, but nonetheless it has its drawbacks. If it is true that in these countries most HIV-infected patients are treated, the number of chronically immuno-deficient carriers of transplanted organs is set to grow. In these patients latent parasitic infections, such as leishmaniasis and toxoplasmosis, can reappear as opportunistic infections. Moreover, the climate changes linked to global warming in temperate countries are extending the insect vector habitats, as is the case of the northward spread of leishmania-transmitting sandflies, assessed by epidemiological surveys of canine leishmaniasis in Italy [2][3][4]. Some additional cases of parasitic infections have also been registered due to "transplant tourism", i.e. travel with the intent of receiving or donating an organ, a practice that is rapidly increasing [5]. A further danger for industrialized countries comes from massive migration of infected subjects from endemic countries: a typical example is the presence of thousands of Trypanosoma cruzi-infected people in North America and Spain [6].In the absence of prophylactic or curative vaccines the only available choice is chemotherapy. However, this relies on drugs which are tens of years old, afflicted with serious disadvantages, such as heavy side-effects, selection of resistant strains, or high production costs. Unfortunately, this situation is not likely to improve in the short t...

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“…[4] Overall, this campaign resulted in only five leads, a low success rate that is unsustainable over long-term drug discovery. In contrast, phenotypic approaches have become quite systematic in the malaria field, [5] where drug resistance has become a huge problem in developing effective therapies.…”

Section: Phenotypic Discoveries In Drug Developmentmentioning

confidence: 99%