Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis

Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage; Plasmodium falciparum; and; Cryptosporidium parvum; in cell-culture studies. Target deconvolution in; P. falciparum; has shown that cladosporin inhibits lysyl-tRNA synthetase (; Pf; KRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both; Pf; KRS1 and; C. parvum; KRS (; Cp; KRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED; 90; = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between; Pf; KRS1 and; Cp; KRS. This series of compounds inhibit; Cp; KRS and; C. parvum; and; Cryptosporidium hominis; in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for; Pf; KRS1 and; Cp; KRS vs. (human); Hs; KRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis

CCQM-K125 Elements in infant formula : Final report

The Key Comparison CCQM-K125 “Elements in Infant Formula” was undertaken to demonstrate the capability of participating national metrology institutes (NMIs) and designated institutes (DIs) in measuring the mass fraction the analytes at mg/kg levels in a test sample of infant formula by various analytical techniques. According to the Inorganic Analysis Working Group’s (IAWG’s) five-year plan, it was recommended to have a key comparison under the measurement service category of food for the year 2015. In this regards, the Government Laboratory, Hong Kong (GLHK) proposed to coordinate a new key comparison and a parallel-run pilot study (CCQM-K125 and CCQM-P159) for the determination of elements in infant formula. At the CCQM IAWG Meeting held in October 2014, the proposed study was agreed by IAWG members to be organised as the fifth benchmarking exercise. It was important for benchmarking to select two exemplary elements which were reasonably easy for many IAWG members to measure. Having further discussed with concerned IAWG members, potassium and copper were selected as the exemplary elements for examination, whereas iodine was an optional element for analysis. This key comparison facilitates claims by participants on the Calibration and Measurement Capabilities (CMCs) as listed in Appendix C of the Key Comparison Database (KCDB) under the Mutual Recognition Arrangement of the International Committee for Weights and Measures (CIPM MRA). Participants are requested to complete the pertinent Inorganic Core Capabilities Tables as a means of providing evidence for their CMC claims. For registration of CCQM-K125, total 25 institutes registered for the examination of the exemplary analytes of potassium and copper, while 12 institutes registered for the optional analyte of iodine. For submission of results, 25 institutes submitted the results for potassium, 24 institutes submitted the results for copper and 8 institutes submitted the results for iodine. The information about registration and submission of participants’ results is summarised in Table A. For examination of potassium and copper, most of the participants used microwave-assisted acid digestion methods for sample dissolution. A variety of instrumental techniques including inductively coupled plasma mass spectrometry (ICP-MS), isotope dilution inductively coupled plasma mass spectrometry (ID-ICP-MS), inductively coupled plasma optical emission spectrometry (ICP-OES), atomic absorption spectrometry (AAS), flame atomic emission spectrometry (FAES) and microwave plasma atomic emission spectroscopy (MP-AES) were employed by the participants for determination. For analysis of iodine, most of the participants used alkaline extraction methods for sample preparation. ICP-MS and ID-ICP-MS were used by the participants for the determination. For this key comparison, inorganic core capabilities were demonstrated by the concerned participants with respect to the methods including ICP-MS (without isotope dilution), ID-ICP-MS, ICP-OES, AAS, FAES and MP-AES on the determination of elements (potassium, copper and iodine) in a food matrix of infant formula