A genetic sensors-based highthroughput screening platform for antimalarial development (MalPharm)

Plasmodium falciparum is the major responsible for the worldwide malaria burden of 200 million cases annually, of which, more than 400 thousand cases are fatal. Elimination and/or control of malaria is therefore a major public health objective for mankind and a top priority for the World Health Organization WHO. At present, global efforts to control and reduce malaria prevalence are based on artemisinin treatments. However, clinical artemisinin resistance has been recently reported in the Southeast Asia. Therefore, development of new antimalarial drugs is a top priority on the worldwide scientific agenda because of its public health implications. However, classical approaches to find new drugs for malaria treatments are still challenging requiring therefore new technologies to achieve it. Development and establishment of biosensors for the monitoring of essential cellular physiological parameters, as calcium oscillation and/or oxidative stress, has been an important recent research advance. Moreover, detection of cellular homeostasis disturbance by drugs is a crucial assessment for the understanding of their action and underlying mechanisms of action. Classical techniques used to perform cellular physiology monitoring are based on fluorescent small molecules compounds like calcium fluorochromes Fluo-3, Fluo-4, etc or membrane potential indicators dyes, Rhodamine 123, TMRM or TMRE to mention a few. Drawbacks on the use of such dyes are centered on the high level of variability due to dye permeability, toxicity, selectivity and specificity which are determinant for the stability of different assays turn it unsuitable for drug high-throughput screening HTS. As a consequence, genetically encoded sensors GES which are fluorescent protein based chimeric proteins with sensing capacity, are being applied for basic science research of physiologic cellular mechanisms, drug actions, as well as, for drug HTS platforms stimulating a truly translational research technology. At present such sensors are being established and developed into Plasmodium falciparum in order to deliver novel antimalarial drugs. The network is a pioneer on this malaria research area establishing the first calcium yellow-chameleon nano-sensors for Plasmodium falciparum and recently redox sensors unpublished. GES has been integrated into the parasites genome, enabling GES expression throughout life cycle and consequently stable and ready-to-monitor parasites at any stage. GES a very appealing technology to be applied into HTS platforms which, when coupled to the novel flow-cytometry technology throughput, generates an antimalarial HTS platform with unprecedented screening capacity. Moreover, implementation of this antimalarial screening platform, due to the low running costs, makes possible the screening of smaller libraries, from Academia and small and medium-sized enterprises SMEs, that still require automatized platforms.

Drug-based Strategies
Product Development

Jul 2018 — Apr 2022

$268,421

Portugal