Antileishmanial Drug Discovery and Development: Time to Reset the Model?

Abstract

Leishmaniasis is a vector-borne parasitic disease caused by Leishmania species. The disease affects humans and animals, particularly dogs, provoking cutaneous, mucocutaneous, or visceral processes depending on the Leishmania sp. and the host immune response. No vaccine for humans is available, and the control relies mainly on chemotherapy. However, currently used drugs are old, some are toxic, and the safer presentations are largely unaffordable by the most severely affected human populations. Moreover, its efficacy has shortcomings, and it has been challenged by the growing reports of resistance and therapeutic failure. This manuscript presents an overview of the currently used drugs, the prevailing model to develop new antileishmanial drugs and its low efficiency, and the impact of deconstruction of the drug pipeline on the high failure rate of potential drugs. To improve the predictive value of preclinical research in the chemotherapy of leishmaniasis, several proposals are presented to circumvent critical hurdles—namely, lack of common goals of collaborative research, particularly in public–private partnership; fragmented efforts; use of inadequate surrogate models, especially for in vivo trials; shortcomings of target product profile (TPP) guides.

In silico-based screening for natural product’s structural analogs as new drugs candidate against leishmaniasis

“…The range of currently available drugs for treating leishmaniasis is relatively small and it includes notably 62.5% of repurposed molecules, while less than 1% of all new drug candidates reached clinical trials in the last decades [42,43]. For these reasons, the investigation of new therapies has been very active recently, whereas a wide range of compounds has been identified as potential hits and leads [44].…”

The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

“…Despite considerable progress in the understanding of the molecular biology of Leishmania sp., antileishmanial chemotherapy remains limited to a few chemical series. Thus, for the last 70 years, pentavalent antimony compounds such as sodium stibogluconate (Pentostam ® , GSK) and meglumine antimoniate (Glucantime ® , Sanofi) have been the first-line treatment for leishmaniases [ 4 ]. Parenteral alternatives to antimonials such as liposomal amphotericin B (AmBisome ® , Gilead) have fewer side effects, while miltefosine (Impavido ® , Zentaris) was the first orally active antileishmanial drug to be developed.…”

“…Parenteral alternatives to antimonials such as liposomal amphotericin B (AmBisome ® , Gilead) have fewer side effects, while miltefosine (Impavido ® , Zentaris) was the first orally active antileishmanial drug to be developed. Paromomycin can also be used, but resistance is developing rapidly, meaning that it is used only in drug combinations [ 4 ]. These currently used drugs are presented in Figure 1 .…”

Selective Anti-Leishmanial Strathclyde Minor Groove Binders Using an N-Oxide Tail-Group Modification

“…It is clearly important for long-term health and well-being to populate the pipeline of new medicines to treat VL, CL and PKDL. The emergence of strains resistant to even the most recently introduced drugs such as miltefosine is critical, and a lack of investment in this neglected tropical disease means that there are few new drugs being developed [ 7 ].…”