25th and 26th October 2010
Work Stream One:
P. falciparum and P vivax / Novel Targets and Classes
The Question:
How to identify and exploit novel targets at all stages of the lifecycle of P falciparum & P vivax.
Background
There is a clear need for the identification and development of antimalarials belonging to novel chemical classes, with novel modes of action and new targets.
Need for new targets / MoA:
Since the publication of the malaria genome, there have been numerous efforts aimed at identifying and validating novel drug targets. Despite these efforts, the reality reflected in the overwhelming majority of antimalarial drug discovery projects is that much of the work is still focused on a limited number of historic targets (the folate and haemoglobin degradation pathways are prime examples), and primarily on the blood stage of the parasite’s lifecycle. There is presumably a wealth of untapped targets in the parasite proteome -or rather proteomes of the various developmental stages that can be targeted.
Need and opportunities for discovery of new chemical classes:
1. Natural products.
The historic success of natural products in antimalarial chemotherapy is well known, and the chemical diversity that is derived from natural products is tremendous. Current drugs that have their foundation in historic natural products include quinine, artemisinin, hydroxynaphthoquinones, doxycycline, clindamycin, and azithromycin. However there are no compounds in Lead Optimisation or preclinical /clinical development that have originated from a natural product in recent years. Many natural products have shown potent antiplasmodial effects but for a variety of reasons these have not been progressed via Hit-to-Lead and Lead Optimization. In addition, there have been recent developments such as the availability of the whole parasite genome and chemical biology that warrant a revisit of the natural product route of drug discovery vis-à-vis target identification. Natural products are better suited in target identification because they generally span a much broader chemical space than synthetic compounds.
2. “Malaria boxes”.
It is anticipated that by the end of 2010 more than 5 million chemical entities will have been screened for antimalarial activity, based on whole cell screens of P. falciparum malaria. The screens have included fully-synthetic libraries (from both commercial sources and Pharma proprietary libraries) and natural product libraries. Activity has been established based on the ability to stop the growth of asexual P. falciparum malaria parasites over a 24- 48hr exposure period in vitro. About 20K compounds are now available that are known to have selective parasiticidal (versus mammalian cell killing) activity, but whose molecular targets are unknown. Many of these chemicals are likely to act through novel pharmacophores on novel molecular targets. This represents a unique resource that must be tapped, but it has its shortcomings (see below, “Key Challenges”).
The Challenge
The challenges in this context are many, and include:-
- Diversifying the life cycle stages that are targets for chemotherapeutic intervention. At present, the vast majority of drug targets the metabolically active trophozoite/schizont stages of the P. falciparum erythrocytic cycle.
- Can biology/bio-informatics propose targets that act at different stages (e.g. early asexual erythrocytic stages, sexual or liver stages)?
- Can cellular screening assays be developed on such different stages? If so, should the malaria boxes be screened on these? Or should new cellular screens be implemented (e.g. gametocytogenesis, early ring to trophozoite development) perhaps using high content analysis?
- Identify malaria box compounds acting on novel targets. It is likely that compounds with novel MoA are hidden within the malaria boxes.
- Is it worth engaging on screening the malaria boxes on selected putative novel molecular targets?
- What other strategies could be developed to address this challenge?
- Include P. vivax in the drug discovery pipeline. Malaria boxes have been selected on P. falciparum, but P. vivax requires urgent attention.
- In the absence of a P. vivax culture system, would it be worthwhile to implement biochemical screens of the malaria boxes on putative targets?
- Can the P. cynomolgi system represent a usable alternative for P. vivax?
- Accelerate and integrate the screening of natural products
- What are the best ways to screen natural products (target vs. phenotypic whole cell screenings) and in what form?
- What unique criteria, that are different from synthetic compounds, should we develop for selecting natural products for hit to lead medicinal chemistry progression?
- How can we best utilize natural products in target identification?
- What are the challenges facing antimalarial drug discovery efforts based on natural products?
- Can we coordinate efforts in this area?
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