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Drug Targets, Drug Effectors, and Drug Targeting and Delivery

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Book cover Drug Resistance in Leishmania Parasites

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Summary

The chemotherapy of leishmaniases has undergone significant improvements during the last decade with the use of liposomal amphotericin B formulation (AmBisome®) and miltefosine as the first orally active drug. However, whatever the proposed treatment, limitations such as adverse effects and the emergence of drug resistance justify the search for new therapies. One way to overcome these limitations is to improve the classical treatments by drug association, which appears to be successful at the clinical level for leishmaniasis, mainly by associating AmBisome® with miltefosine. Another approach consists in designing new formulations of classical drugs able to limit adverse effects by concentrating the drug at its site of action in the case of visceral leishmaniasis or, on the other hand, by spreading the drug over the whole body to treat diffuse leishmaniasis. Progress in nanotechnology will open the way for new low-cost formulations during the next decade.

The identification of new targets that are specific of the parasite remains a priority to design new chemical leads having low toxicity for the host. Such targets should be validated as necessary for the parasite survival. However, common enzyme systems present in both the parasite and the host should not be neglected since alpha-difluoromethylornithine is a successful example of this approach in the field of human African trypanosomiasis. The knowledge of the molecular and mechanistic differences between parasite and host functional proteins, completed by computer-aided drug design, is still awaited for the emergence of new drugs.

The identification of new leads includes systematic evaluation of extracts from natural origin based on bio-guided fractionation. Compounds obtained from such investigations, such as licochalcone and quinolines, are in predevelopment. More efforts in this direction should yield results, taking advantage of the biodiversity not only of plants but also of animals. In parallel to this approach, many chemical series known for their antileishmanial activities are being revisited using rational pharmacomodulation in order to improve their bioavailability, to diminish their toxicity and to focus the drug on its target. Another promising approach is the design of multi-target-directed ligands in order to affect at least two targets within the parasite. All these investigations should provide new tools for the antileishmanial chemotherapy of tomorrow.

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Authors and Affiliations

  1. Groupe Chimiothérapie Antiparasitaire, UMR 8076 CNRS, Faculté de Pharmacie, Université Paris-Sud 11, 92290, Châtenay-Malabry, France

    Philippe M. Loiseau

  2. CNRS UMR 8612, 5 rue J.B. Clément, 92296, Chatenay-Malabry, France

    Gillian Barratt

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  1. Philippe M. Loiseau
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Correspondence to Philippe M. Loiseau .

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  1. Fac. Medicina, Instituto de Medicina Experimental, Universidad Central de Venezuela, Caracas, 1062, Venezuela

    Alicia Ponte-Sucre

  2. Universidad Central de Venezuela, ciudad universitaria, Caracas, 1062, Venezuela

    Emilia Diaz

  3. Universidad Central de Venezuela, ciudad universitaria, Caracas, 1062, Venezuela

    Maritza Padrón-Nieves

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Loiseau, P.M., Barratt, G. (2013). Drug Targets, Drug Effectors, and Drug Targeting and Delivery. In: Ponte-Sucre, A., Diaz, E., Padrón-Nieves, M. (eds) Drug Resistance in Leishmania Parasites. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1125-3_16

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