ThePlasmodium falciparumDrugome And Its Polypharmacological Implications

Abstract

Malaria is a disease contracted by over 200 million people each year, mostly in developing countries. The primary causative agent, Plasmodium falciparum (P. falciparum) has shown increased resistance to existing drugs, hence new treatments are needed quickly. To this end we performed a high-throughput systems-level analysis, mapping existing FDA drugs with the potential for repurposing against targets from the P. falciparum structural proteome. The resulting P. falciparum drugome (P.falciparum-drugome) was used to prioritize potential new anti-malaria candidate targets and highlight some novel FDA approved drugs that have apparent anti-malaria effects for possible use as multi-target therapeutics.is now widely accepted 2 . Stated another way, a drug response is a consequence of complex interactions between multiple intracellular and extracellular components. Thus designing drugs assuming multiple targets is becoming the new rational approach to drug discovery, but requires a system level view of drug action. Systems pharmacology provides that view through a systematic understanding of drug action by integrating systems biology (including biological network analysis 3 ), bioinformatics and cheminformatics approaches.Simultaneously, network analysis approaches of a different kind have proven useful for organizing high-dimensional biological datasets and extracting meaningful information. Such network approaches in systems pharmacology can provide a global view of drug relationships, identify new drug targets as well as therapeutic strategies, and improve our understanding of the side effects and alternative uses of current drugs 3-4 . Here we exploit such a network approach in determining the P. falciparum drugome, a structural proteome-wide drug-target interaction network that forms a basis for exploring alternative treatments for malaria.Malaria is one of the most devastating and widespread tropical parasitic diseases and is most prevalent in developing countries. The World Health Organization has estimated that over 200 million cases of malaria occur annually 5 ; in 2010, around 655,000 deaths were reported, but this is likely a significant underestimate. Approximately 87% of these deaths were children under the age of five 6 . To reduce the number of malaria infections and to reduce the death toll is an urgent priority.Malaria is caused by the Plasmodium parasite, which is transmitted by a mosquito vector. In humans, the parasites multiply in the liver, and then infect red blood cells. There are five species that are known to infect humans: P. falciparum, Plasmodium vivax, Plasmodium ovalae, Plasmodium malariae and Plasmodium knowelsi. Among these five species, the parasite P. falciparum is the most dangerous, with the highest rates of complications and mortality.Currently, there are no approved vaccines available and given increasing drug resistance, finding novel anti-malarial drugs and associated targets appears the most efficient way to fight malaria 7 .Previously Gamo et al. 8 screened nearly 2 million com...

<p>Antimalarial Drug Resistance and Novel Targets for Antimalarial Drug Discovery</p>

“… 2 Malaria is among the most devastating and widespread tropical parasitic diseases in which most prevalent in developing countries. 3 Malaria is caused by the Plasmodium parasite, which is transmitted by the bite of a mosquito vector. Five species are known to infect humans: P. falciparum, Plasmodium vivax, Plasmodium ovalae, Plasmodium malariae , and Plasmodium knowelsi .…”

“…The parasite P. falciparum causes the most dangerous, with the highest rates of complications and mortality. 3 Antimalarial drug resistance results in a global resurgence of malaria making a major threat to malaria control. Widespread and indiscriminate use of antimalarial drugs contributes to malaria parasites to evolve mechanisms of resistance.…”

Antimalarial Activity of Methanolic Extracts and Solvent Fractions of Combretum molle Leaves in Plasmodium berghei Infected Mice

“… 5 It is among the foremost devastating and widespread tropical diseases and most prevalent in developing countries. 6 Drug resistance of plasmodium species to available drugs causes a big threat to its control. 7 WHO 2018 reported 219 million malaria cases worldwide and in 2017 200 million malaria cases in Africa.…”

In vivo antimalarial activity of the crude leaf extract of Combretum molle against Plasmodium berghei in mice

“…Malaria control requires prevention, primarily vector control, and prompts treatment with effective antimalarial drugs [5] . Malaria is among the most devastating and widespread tropical parasitic diseases in which most prevalent in developing countries [6] . Antimalarial drug resistance results in a global resurgence of malaria making a major threat to malaria control.…”