Challenges and recent progress in drug discovery for tropical diseases

Infectious tropical diseases have a huge effect in terms of mortality and morbidity, and impose a heavy economic burden on affected countries. These diseases predominantly affect the world’s poorest people. Currently available drugs are inadequate for the majority of these diseases, and there is an urgent need for new treatments. This Review discusses some of the challenges involved in developing new drugs to treat these diseases and highlights recent progress. While there have been notable successes, there is still a long way to go.</p

P113 is a merozoite surface protein that binds the N terminus of Plasmodium falciparum RH5.

Invasion of erythrocytes by Plasmodium falciparum merozoites is necessary for malaria pathogenesis and is therefore a primary target for vaccine development. RH5 is a leading subunit vaccine candidate because anti-RH5 antibodies inhibit parasite growth and the interaction with its erythrocyte receptor basigin is essential for invasion. RH5 is secreted, complexes with other parasite proteins including CyRPA and RIPR, and contains a conserved N-terminal region (RH5Nt) of unknown function that is cleaved from the native protein. Here, we identify P113 as a merozoite surface protein that directly interacts with RH5Nt. Using recombinant proteins and a sensitive protein interaction assay, we establish the binding interdependencies of all the other known RH5 complex components and conclude that the RH5Nt-P113 interaction provides a releasable mechanism for anchoring RH5 to the merozoite surface. We exploit these findings to design a chemically synthesized peptide corresponding to RH5Nt, which could contribute to a cost-effective malaria vaccine

Identification of Rhoptry Trafficking Determinants and Evidence for a Novel Sorting Mechanism in the Malaria Parasite Plasmodium falciparum

The rhoptry of the malaria parasite Plasmodium falciparum is an unusual secretory organelle that is thought to be related to secretory lysosomes in higher eukaryotes. Rhoptries contain an extensive collection of proteins that participate in host cell invasion and in the formation of the parasitophorous vacuole, but little is known about sorting signals required for rhoptry protein targeting. Using green fluorescent protein chimeras and in vitro pull-down assays, we performed an analysis of the signals required for trafficking of the rhoptry protein RAP1. We provide evidence that RAP1 is escorted to the rhoptry via an interaction with the glycosylphosphatidyl inositol-anchored rhoptry protein RAMA. Once within the rhoptry, RAP1 contains distinct signals for localisation within a sub-compartment of the organelle and subsequent transfer to the parasitophorous vacuole after invasion. This is the first detailed description of rhoptry trafficking signals in Plasmodium

Mechanical characterisation of polymer of intrinsic microporosity PIM-1 for hydrogen storage applications

Polymers of intrinsic microporosity (PIMs) are currently attracting interest due to their unusual combination of high surface areas and capability to be processed into free-standing films. However, there has been little published work with regards to their physical and mechanical properties. In this paper, detailed characterisation of PIM-1 was performed by considering its chemical, gas adsorption and mechanical properties. The polymer was cast into films, and characterised in terms of their hydrogen adsorption at −196 °C up to much higher pressures (17 MPa) than previously reported (2 MPa), demonstrating the maximum excess adsorbed capacity of the material and its uptake behaviour in higher pressure regimes. The measured tensile strength of the polymer film was 31 MPa with a Young’s modulus of 1.26 GPa, whereas the average storage modulus exceeded 960 MPa. The failure strain of the material was 4.4%. It was found that the film is thermally stable at low temperatures, down to −150 °C, and decomposition of the material occurs at 350 °C. These results suggest that PIM-1 has sufficient elasticity to withstand the elastic deformations occurring within state-of-the-art high-pressure hydrogen storage tanks and sufficient thermal stability to be applied at the range of temperatures necessary for gas storage applications

Post-synthetic Ti Exchanged UiO-66 Metal-Organic Frameworks that Deliver Exceptional Gas Permeability in Mixed Matrix Membranes

Gas separation membranes are one of the lowest energy technologies available for the separation of carbon dioxide from flue gas. Key to handling the immense scale of this separation is maximised membrane permeability at sufficient selectivity for CO2 over N2. For the first time it is revealed that metals can be post-synthetically exchanged in MOFs to drastically enhance gas transport performance in membranes. Ti-exchanged UiO-66 MOFs have been found to triple the gas permeability without a loss in selectivity due to several effects that include increased affinity for CO2 and stronger interactions between the polymer matrix and the Ti-MOFs. As a result, it is also shown that MOFs optimized in previous works for batch-wise adsorption applications can be applied to membranes, which have lower demands on material quantities. These membranes exhibit exceptional CO2 permeability enhancement of as much as 153% when compared to the non-exchanged UiO-66 mixed-matrix controls, which places them well above the Robeson upper bound at just a 5 wt.% loading. The fact that maximum permeability enhancement occurs at such low loadings, significantly less than the optimum for other MMMs, is a major advantage in large-scale application due to the more attainable quantities of MOF needed

Enhanced selectivity in mixed matrix membranes for CO2 capture through efficient dispersion of amine-functionalized MOF nanoparticles

Mixed matrix membranes (MMMs) for gas separation applications have enhanced selectivity when compared with the pure polymer matrix, but are commonly reported with low intrinsic permeability, which has major cost implications for implementation of membrane technologies in large-scale carbon capture projects. High-permeability polymers rarely generate sufficient selectivity for energy-efficient CO2 capture. Here we report substantial selectivity enhancements within high-permeability polymers as a result of the efficient dispersion of amine-functionalized, nanosized metal–organic framework (MOF) additives. The enhancement effects under optimal mixing conditions occur with minimal loss in overall permeability. Nanosizing of the MOF enhances its dispersion within the polymer matrix to minimize non-selective microvoid formation around the particles. Amination of such MOFs increases their interaction with thepolymer matrix, resulting in a measured rigidification and enhanced selectivity of the overall composite. The optimal MOF MMM performance was verified in three different polymer systems, and also over pressure and temperature ranges suitable for carbon capture