Malaria; Synthetic biology

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Malaria	transferred from chimpanzees 10000 years ago definitive host and vector: mosquito (female anopheles mosquito) intermediate host: humans pathogen: Plasmodium spp over 11 species can infect humans 5 major: falciparum, ovale, vivax, knowlesi, malariae *falciparum is most virulent, causes cerebral malaria. In 2012, there were about 207 million malaria cases (with an uncertainty range of 135 million to 287 million) and an estimated 627 000 malaria deaths (with an uncertainty range of 473 000 to 789 000).
Life cycle	Mosquito bites uninfected human, releasing material from salivary gland that contains primitive parasite form, sporozoites. Sporozoites settle in the blood for a few minutes then travel to the liver where they multiply asexually forming hepatic schizonts. They multiply within the schizonts as merozoites with each schizont containing tens of thousands of merozoites. The cells rupture releasing merozoites into the blood stream causing malaria symptoms (chills, fever followed by sweating). Some merozoites remain in the liver cell for a long time causing relapses. Merozoites invade red blood cells and make a choice to go into the erythrocytic cycle (multiply asexually, RBC ruptures releasing fresh batch of merozoites that make a choice... infect RBCs... Cell rupture and release of merozoites usually coincide with onset of symptoms) and differentiation into sexual stages of the parasite, male or female gametocytes. The gametocytes circulate in the blood. Mosquito comes for blood meal, takes up infected blood. male and female gametocytes mature in the gut to form male and female gametes that fuse into a zygote. The zygote matures into an ookinette tha burrows into the mosquito stomach wall, differentiates into oocyst which divides to become sporozoites. After about 5-7 days, about a thousand sporozoites are released from each oocyst, they travel to the salivary glands ready to infect another human.
treatment	Primitive treatments... Drugs: Quinine and derivatives, bitter tasting; mefloquine, chloroquine... Artemisinin
What has been driving malaria drug discover	military
Artemisinin	Dr Tu Youyou, Project 523 Artemisia annua extracts cleared malaria parasites faster than any drug in history As of 2006, quinine is no longer recommended by the WHO as a first-‐line treatment for malaria • Artemisinin-‐combination therapies – ACTs - are now standard treatment worldwide for falciparum malaria • A second drug (e.g. quinine, mefloquine), given as part of a combination, prevents resistant parasites surviving
Mode of Action	Artemisinin contains an unusual peroxide bridge, intracellular free iron induces a chemical reaction in the peroxide bridge generating carbon-based free radicals, plasmodium parasites sequester iron internally, artemisinin enters the parasite and combines with the iron to form free radicals rupturing the parasites
Anticancer therapy	cancer cells sequester free iron than normal cells. Artemisinin and its analogues selectively induce apoptosis in cancer cells. Currently being developed to be more potent and target-selective; less side effects than traditional chemotherapeutic agents
No longer used as a drug?	Artemisinin is now used as a starting compound for the production of 'artemisins' e.g. dihydroartemisin, artesunate, artemether DHA more potent than Artemisinin. Artesunate particularly useful since it is water soluble and can be administered by injection
Pharmacology	Artemisinin is a schizontocide, also has gametocidal activity e.g. in P falciparum. Less efficient spread of the pathogen since sexual stages are killed.
Issues	Most people who need ACTs do not receive them because of the financial situation of the countries with people most prone to malaria. 2007-2008, only 15% of children under 5 who needed ACTs received them
Why	Cost of ACTs, major one is artemisin; Artemisinin is a natural product, many bottlenecks; supply chain challenge 2007, boom and bust of artemisinin supply because farmers produced too much, prices plummeted. Natural production is not meeting demand
Ways?	Natural, Chemical or Recombinant
Natural: Artemisia annua	Labour intensive, long growing season(12-18 months), sensitive to cultivating conditions; humidity, salinity, temperature, rainfall; artemisinin recovery is low (5Kg per 1000Kg of dried leaves), supply is vulnerable to several conditions: climate change, political unrest, adverse weather conditions, unforeseen circumstances, potential crop failures, past trend of boom and bust; artemisinin extraction and purification is costly and potentially unsafe, environmentally demanding (use of organic solvents; hexane and petroleum ether)
Chemical: artemisin	achieved in 1983; “Long, arduous, and economically nonviable”... Jay Keasling, 2008
Chemical; alternatives- synthetic peroxides	Trioxolane; In their sub-cellular localization and peroxidative effects, 1,2,4-trioxolane probes behave much like artemisinin-based probes studied previously. Our results are consistent with a role for adamantane-derived carbon-centered radicals in the antimalarial action of 1,2,4-trioxolanes, as hypothesized previously on the basis of chemical reactivity studies... Hartwig et al., 2011
Trioxolane	Arterolane at daily doses of 100 and 200 mg is a rapidly acting, effective, and safe synthetic antimalarial drug, which may potentially represent an alternative to artemisinin derivatives in antimalarial combination therapy... Valecha et al., 2010
Trioxolane: Arterolane maleate with piperaquine	Arterolane maleate in combination with long-acting piperaquine phosphate is under development as an antimalarial product in line with WHO-recommended combination therapy for the treatment of uncomplicated P. falciparum malaria.
Avoiding resistance	In malaria treatment guidelines, the WHO identified the rationale of combining antimalarials that have different modes of action, to prevent development of resistance and to optimize antimalarial therapy ... Valecha et al., 2010
vote for arterolane and other drugs	In view of the emerging resistance against the existing antimalarial agents and increased Parasite Clearance Time PCTs following artemisinin-based combination therapy, there is an urgent need to develop new alternative drugs. A fully synthetic drug such as arterolane, which has a activity profile similar to that of the artemisinins, provides an important potential in such an endeavor.... Valecha et al., 2010
Key features included low product costs requiring a straightforward synthesis and simple formulation approaches, a maximum 3-day treatment regimen with once-daily administration necessitating good potency and pharmacokinetic properties, low potential for toxicity and no evidence for resistance development... Vennerstrom et al., 2004	Arterolane (RBx 11160) maleate is a new, fully synthetic 1,2,4-trioxolane with a peroxidic pharmacophore and is a rapidly acting oral antimalarial drug In comparison to the semi-synthetic artemisinins (Fig. 1a), the selected 1,2,4-trioxolane drug development candidate (trioxolane 7; also known as OZ277 or RBx-11160, Fig. 1e) exhibits structural simplicity, an economically feasible and scalable synthesis, superior antimalarial activity and an improved biopharmaceutical proﬁle
SynriamTM	released by Ranbaxy in 2012 for treatment of P. vivax, successfully completed phase III trials in India now for P. falciparum and P. vivax malaria.
Artemisinin Resistance	Parasite resistance to artemisinin, the core compound in WHO-recommended combination treatments for uncomplicated malaria, has been detected in 4 countries of south east Asia: Cambodia, Myanmar, Thailand and Viet Nam. However, artemisinin-based combination therapies remain highly effective in almost all settings, as long as the partner drug in the combination is locally effective.
Synthetic	Artemisinin is a sesquiterpene(15C).

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