Challenges in drug discovery targeting TriTryp diseases with an emphasis on leishmaniasis

Abstract

Tritryps diseases are devastating parasitic neglected infections caused by Leishmania spp., Trypanosoma cruzi and Trypanosoma brucei subspecies. Together, these parasites affect more than 30 million people worldwide and cause high mortality and morbidity. Leishmaniasis comprises a complex group of diseases with clinical manifestation ranging from cutaneous lesions to systemic visceral damage. Antimonials, the first-choice drugs used to treat leishmaniasis, lead to high toxicity and carry significant contraindications limiting its use. Drug-resistant parasite strains are also a matter for increasing concern, especially in areas with very limited resources. The current scenario calls for novel and/or improvement of existing therapeutics as key research priorities in the field. Although several studies have shown advances in drug discovery towards leishmaniasis in recent years, key knowledge gaps in drug discovery pipelines still need to be addressed. In this review we discuss not only scientific and non-scientific bottlenecks in drug development, but also the central role of public-private partnerships for a successful campaign for novel treatment options against this devastating disease.

Toxicity and Anti-promastigote Activity of Benzoxazinoid Analogs Against Leishmania (Viannia) braziliensis and Leishmania (Leishmania) infantum

“…Various problems associated with the current antileishmanial therapy, i.e., high toxicity, serious adverse effects, long course, storage, and access difficulties; together with the medical, epidemiological and social importance of this zoonosis, highlights the need to study the potential antiparasitic of Bex-derived compounds against the genus Leishmania. 1,[7][8][9] Here, a set of C-2 substituted Bexs, synthesized using the pyridoxazinone and benzoxazinone core as described by Lima et al, 18 were evaluated for anti-promastigote activity against L. (V.) braziliensis and L. (L.) infantum.…”

“…In addition patients in need of treatment exhibit a low adherence to treatment plans and there is an insufficient availability of drugs generally in endemic regions. 9 Additionally, Leishmania strains with moderate and complete resistance to pentavalent antimonials and amphotericin B have already been identified in several parts of the world. 10 Problems with available therapies are even more pressing the pharmaceutical industry has neglected to investment in the research and development of new compounds with antileishmanial activity; a class of drugs that has represented less of 1% of drugs researched in the last year by the most prominent companies.…”

“…Currently, the World Health Organization (WHO) recommended the use of some herbal medicines as antileishmanial agents and several studies have determined that the phytoconstituents of these medicinal plants should be considered prototypes for new leishmanicidal drugs. 1,9 Thus, the benzoxazinoids (Bexs), which are allelochemical alkaloids widely distributed among monocotyledons of the Gramineae family, stand out as a potential targets in the search for new antileishmanial agents. 12 Bexs are characterized by the presence of a 2-hydroxy-2H-1,4benzoxazin-3(4H)-one skeleton and are known to show anti-inflammatory, antinociceptive, reproductive and immune stimulatory, antitumor and appetite suppressor activities.…”

Canine and Human Leishmaniasis: Disease Progression to Brazilian Urbanized Areas

“…In general, leishmaniasis chemotherapy is very complex not only for dogs, but also for humans [58]. Given the prohibition of treating dogs with the same drugs used to treat humans in Brazil for a long period,a great mission capacity of L. (L.) infantum from maned wolves (Chrysocyon brachyurus) and vinegar dogs (Speothos venaticus) infected without symptoms to invertebrate hosts, probably sustaining the natural parasitic cycle [42].…”

<p><em>Leishmania donovani</em> Growth Inhibitors from Pathogen Box Compounds of Medicine for Malaria Venture</p>

“…13 Therefore, shortterm strategies such as searching for novel anti-leishmanial leads by phenotypic screening is an important approach to discover and develop drugs against leishmaniasis. [14][15][16] Drug repurposing, compared to development of new drugs, is time efficient and cost effective. 16 The art of drug repurposing usually starts with developing a method for screening and proceeds to hit identification, lead optimization and clinical studies.…”