21 research outputs found
Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach
Malaria is an infectious disease caused by parasites of the genus Plasmodium, which leads to approximately one million deaths per annum worldwide. Chemical validation of new antimalarial targets is urgently required in view of rising resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase, which catalyses the attachment of the fatty acid myristate to protein substrates (N-myristoylation). Here, we report an integrated chemical biology approach to explore protein myristoylation in the major human parasite P. falciparum, combining chemical proteomic tools for identification of the myristoylated and glycosylphosphatidylinositol-anchored proteome with selective small-molecule N-myristoyltransferase inhibitors. We demonstrate that N-myristoyltransferase is an essential and chemically tractable target in malaria parasites both in vitro and in vivo, and show that selective inhibition of N-myristoylation leads to catastrophic and irreversible failure to assemble the inner membrane complex, a critical subcellular organelle in the parasite life cycle. Our studies provide the basis for the development of new antimalarials targeting N-myristoyltransferase
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SCDAP/RELAP5 independent peer review
The SCDAP/RELAP5 code has been developed for best-estimate transient simulation of light-water-reactor coolant systems during severe accidents. The newest version of the code is SCDAP/RELAP5/MOD3. The US Nuclear Regulatory Commission (NRC) decided that there was a need for a broad technical review of the code by recognized experts to determine overall technical adequacy, even though the code is still under development. For this purpose, an eight-member SCDAP/RELAP5 Peer Review Committee was organized, and the outcome of the review should help the NRC prioritize future code-development activity. Because the code is designed to be mechanistic, the Committee used a higher standard for technical adequacy than was employed in the peer review of the parametric MELCOR code. The Committee completed its review of the SCDAP/RELAP5 code, and the findings are documented in this report. Based on these findings, recommendations in five areas are provided: (1) phenomenological models, (2) code-design objectives, (3) code-targeted applications, (4) other findings, and (5) additional recommendations