2015 Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine 2015 was awarded to William C. Campbell, Satoshi Ōmura and Youyou Tu.
William Campbell and Satoshi Ōmura shared one-half of the prize for their discoveries of a new drug, Avermectin, that was highly effective against a spectrum of parasitic worm infections. The derivatives of this compound are currently being used to eradicate and prevent the transmission of River Blindness and Lymphatic Filariasis.
Youyou Tu was awarded the other half of the Nobel Prize for her discovery of Artemisinin, a drug that has become a frontline treatment for malaria and has significantly reduced the mortality rates for patients suffering from this disease worldwide.
In celebration, NPG is making available a range of articles from its journal archives that feature these scientists’ remarkable achievements and highlight recent progress in these fields.
Image Credit: EYE OF SCIENCE/SCIENCE PHOTO LIBRARY
News and Comments
Entry of the antimalarial drug precursor semi-synthetic artemisinin into industrial production is the first major milestone for the application of synthetic biology. In this Review, Paddon and Keasling discuss the metabolic engineering and synthetic biology approaches that were used to engineerEscherichia coli and Saccharomyces cerevisiaeto synthesize a precursor of artemisinin, which should aid the development of other pharmaceutical products.
Long ignored by pharmaceutical companies and global health agencies alike, 'neglected tropical diseases' devastate people in the poorest parts of the world. But they're finally getting the attention they deserve, reports Apoorva Mandavilli.
In this Science and Society article, Carl Nathan reviews historical collaborations between industry and academic instiutions that developed antimicrobials, and discusses similar strategies that have recently emerged to tackle the crisis of antimicrobial resistance.
The screening of natural products for lead molecules is an attractive strategy, as most natural products fall within biologically relevant chemical space. In this Review, Harvey, Edrada-Ebel and Quinn discuss how advanced screening, metabolomics and metagenomics approaches can be used in the identification, validation and production of naturally sourced compounds, and highlight examples of naturally derived antimicrobials and inhibitors of protein–protein interactions.
Reviews and Research
Two semi-synthetic processes for the production of the antimalarial natural product artemisinin have been developed by applying the principles of green chemistry. Solvent manipulation allows catalyst recycling and reduction of waste, ultimately leading to a purification-free process with lower environmental and economic costs; a potential contribution to the world-wide fight against malaria.
In one of the largest public health campaigns in history, a concerted malaria control campaign has been under way in sub-Saharan Africa for the past 15 years. Billions of dollars have been invested to provide interventions such as bed nets and antimalarial drugs but the overall effect on malaria burden remains unclear. This study uses field data from 30,000 population clusters in a sophisticated space–time modelling framework to quantify the changing Plasmodium falciparum risk (a 40% decline in case incidence since 2000) and the role of malaria interventions (around 700 million cases averted). Although below target levels, the current campaign has substantially reduced the incidence of malaria across the continent. Continued success will depend upon increasing access to these interventions, and maintaining their effectiveness in the face of insecticide and drug resistance.
With artemisinin resistance spreading, there is an urgent need to develop new therapeutics to target Plasmodium falciparum, the causative agent of malaria. Here Ian Gilbert and colleagues report the discovery of a compound (DDD107498) with antimalarial activity against multiple life-cycle stages of the parasite and good pharmacokinetic and safety properties. It is non-mutagenic and has potential for both single-dose treatment and once-weekly chemoprotection. DDD107498 acts through inhibition of cytosolic protein synthesis, with translation elongation factor eEF2 as its target.
Artemisinin-based combination therapies are the treatment of choice for uncomplicated Plasmodium falciparum malaria, but the supply of plant-derived artemisinin can sometimes be unreliable, causing shortages and high prices. This manuscript describes a viable industrial process for the production of semisynthetic artemisinin, with the potential to help stabilize artemisinin supply. The process uses Saccharomyces cerevisiae yeast engineered to produce high yields of artemisinic acid, a precursor of artemisinin. The authors have also developed an efficient and scalable chemical process to convert artemisinic acid to artemisinin.
Dominic Kwiatkowski and colleagues report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin. They identify markers of a genetic background on which kelch13 mutations conferring artemisinin resistance are likely to emerge.
The nuclear Farnesoid X receptor (FXR) regulates bile acid and cholesterol production. Here Jin et al. identify the clinically approved antiparasitic drug ivermectin as a novel FXR ligand and show that it has antidiabetic effects in mice.
Editing the genome of a malarial parasite with Cas9 validates a drug-resistance polymorphism
Single guide RNAs driven by a T7 promoter target Cas9 to two endogenous loci, leading to fast and efficient genome editing in the malaria parasite P. falciparum.
New X-ray crystal structure and immunoanalyses of alanyl aminopeptidase N (AnAPN1), a gut antigen of the Anopheles mosquito vector of Plasmodium falciparum, reveal how AnAPN1-specific antibodies block transmission of the malarial parasite.
The emergence of artemisinin resistance is a major threat to world-wide malaria treatment and control and although artemisinins have been linked with a variety of cellular factors, there has been no consensus on the relevant biochemical targets or mechanisms underpinning resistance. Here Kasturi Haldar and colleagues show that artemisinins target the parasite phosphatidylinositol-3-kinase (PfPI3K) to inhibit the production of phosphatidylinositol 3-phosphate (PI3P). Mutation in PfKelch13, a previously identified resistance marker, increases levels of PfPI3K in both clinically derived strains and in engineered laboratory parasites. This work points to PfPI3K as the key mediator of artemisinin resistance and a target for malaria elimination.
Screening for new anthelmintic compounds that are active against parasitic nematodes is costly and labour intensive. Here, the authors use the non-parasitic nematode Caenorhabditis elegansto identify 30 anthelmintic lead compounds in an effective and cost-efficient manner.