**5. Conclusions**

This last decade, the international mobilization dedicated to antimalarial strategies has regularly increased, allowing many countries to undertake or strengthen effective fight against the parasite, the disease and the vectors, and leading to a slowing-down, even a decline in some place, of malaria all over the world, thanks to the usage of impregnated bed nets and the setting-up of artemisinin combination therapies. However, the resistance of the insect vectors to insecticides and of the parasites to the current antimalarial drugs, especially to artemisinin derivatives, is still increasing and problematic since no new class of antimalarials has been introduced since 1996. The current global antimalarial drug development shows that the pipeline of antimalarials is rather strong in term of initiatives but also rather weak in term of novelty of mechanism of action that is necessary to circumvent resistance. This situation results in an urgent need for new drugs with original mechanisms of action. This last decade has also seen a considerable increase in our understanding of malaria parasite biochemistry that has allowed the identification of many potential targets for new drugs such as apicoplast metabolisms, proteases, kinases, transporters… That has been made possible thanks to the decrypted genomes of several *Plasmodium* species, to our ability to genetically validate potential drug targets and to the access to the transcriptomic and proteomic technologies that offer new opportunities to study the impact of drugs on the entire parasite metabolism.

These advances associated to the setting-up of high-throughput screening platforms on whole-cells or on specific parasite targets, and to the access to large chemical libraries with broad chemical diversity have seen the recent emergence of new potential antimalarial drugs with original molecular frameworks and mechanisms of action, that are auspicious for the future of antimalarial drug development. We are however facing important challenges in the next decade to propose efficient global antimalarial drug development. This will require :


Finally, it must be kept in mind that for any promising molecule that will be selected, administration to patients will be the acid test. That is why development of small, easy to manage *in vivo* models as close to humans as possible remains a really challenging part of any therapeutic molecule development. Efforts are currently made to achieve these goals.

### **6. References**

340 Malaria Parasites

This last decade, the international mobilization dedicated to antimalarial strategies has regularly increased, allowing many countries to undertake or strengthen effective fight against the parasite, the disease and the vectors, and leading to a slowing-down, even a decline in some place, of malaria all over the world, thanks to the usage of impregnated bed nets and the setting-up of artemisinin combination therapies. However, the resistance of the insect vectors to insecticides and of the parasites to the current antimalarial drugs, especially to artemisinin derivatives, is still increasing and problematic since no new class of antimalarials has been introduced since 1996. The current global antimalarial drug development shows that the pipeline of antimalarials is rather strong in term of initiatives but also rather weak in term of novelty of mechanism of action that is necessary to circumvent resistance. This situation results in an urgent need for new drugs with original mechanisms of action. This last decade has also seen a considerable increase in our understanding of malaria parasite biochemistry that has allowed the identification of many potential targets for new drugs such as apicoplast metabolisms, proteases, kinases, transporters… That has been made possible thanks to the decrypted genomes of several *Plasmodium* species, to our ability to genetically validate potential drug targets and to the access to the transcriptomic and proteomic technologies that offer new opportunities to

These advances associated to the setting-up of high-throughput screening platforms on whole-cells or on specific parasite targets, and to the access to large chemical libraries with broad chemical diversity have seen the recent emergence of new potential antimalarial drugs with original molecular frameworks and mechanisms of action, that are auspicious for the future of antimalarial drug development. We are however facing important challenges in the next decade to propose efficient global antimalarial drug development.

1. Ability to propose efficient heterologous expression and folding systems to produce recombinant active proteins for targets, in order to set up high-throughput screening assays or to obtain 3D-dimensional structure elucidations using X-ray crystallography

2. Development of researches on *P. vivax*, which can be considered as a neglected disease when compared to the efforts developed for *P. falciparum* whereas *P. vivax* infection is

3. Strengthening researches on drugs acting on the liver parasite stages, including hypnozoites, and the parasite transmission stages, in order to propose an antimalarial drug strategy not only acting on the disease by itself due to the intraerythrocytic parasite development, but also acting on the disease transmission and the disease

Finally, it must be kept in mind that for any promising molecule that will be selected, administration to patients will be the acid test. That is why development of small, easy to manage *in vivo* models as close to humans as possible remains a really challenging part of any therapeutic molecule development. Efforts are currently made to achieve these

more widespread and remains an important cause of morbidity.

study the impact of drugs on the entire parasite metabolism.

**5. Conclusions** 

This will require :

goals.

for drug design.

relapse in the case of *P. vivax*.


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