Recent Advances in Anti-Schistosomiasis Drug Discovery

Schistosomiasis, a parasitic disease caused by infection by helminths of the Schistosoma genus, affects over 200 million people, primarily in the developing world. Treatment of this disease largely relies on one drug, praziquantel. Although this drug is cheap, safe, and effective, the looming prospect of drug resistance makes the development of a pipeline of anti-schistosomiasis drugs a priority. Many new drug leads have arisen from screening existing sets of compounds such as the Open Access Boxes developed by the Medicines for Malaria Venture (MMV) in collaboration with the Drugs for Neglected Diseases Initiative (DNDI). Other leads have been found through work focused on druggable targets such as kinases, histone deacetylases, proteases, and others. This chapter will discuss recent work concerning the discovery and development of novel anti-schistosomiasis drug leads from many sources

Open Source Drug Discovery - Highly Potent Antimalarial Compounds Derived from the GlaxoSmithKline Tres Cantos Arylpyrroles

The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate and patents were not sought. One chemical sub-series was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second sub-series displayed high potency, including activity within a late stage gametocyte assay, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work

Crystalline cyclic peptide nanotubes at interfaces

The assembly, orientation, and structural features of nanoscale tubes composed of cyclic peptides, formed at the air−water interface, were detected by grazing incidence X-ray diffraction (GIXD). The peptide cyclo-[(l-Phe-d-N-MeAla-)4] (1) exhibits two-dimensional crystallinity in which the plane of the peptide ring is parallel to the water interface. The peptide cyclo-[(l-Trp-d-Leu)3-l-Ser-d-Leu] (2) forms predominantly planar aggregates composed of several tubes, lying with their long axes parallel to the air−water interface. In contrast, the peptide cyclo-[(l-Trp-d-Leu)4] (3) exhibits a very low tendency to form ordered two-dimensional arrays of nanotubes. Films of peptides 2 and 3 as well as their mixtures with the phospholipid DPPA were transferred onto a solid support and visualized by scanning force microscopy (SFM)