NMR spectroscopic infrastructure for biological and pharmaceutical sciences

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This year, UofM and UMIST merge. This bid involves all the main high resolution NMR spectroscopy components of the new merged institution, viz. School of Pharmacy and Pharmaceutical Sciences SPPS (RAE Best 5*), Chemistry (RAE 5), Biomolecular Sciences (RAE 5) focusing on biologically and pharmaceutically directed uses of NMR. This proposal is to support coordinated NMR-based research in the new unified Manchester University. The theme is the use of NMR methods for pharmaceutical and biological sciences (drug design and action, drug delivery, pharmaceutical biological targets). In contrast to our previous bid (REI2003, 20581), this proposal integrates high resolution NMR science across the whole of the new Manchester University. The applicants are also participants in projects in solid-state NMR and MR imaging, but these fall outside the scope of this proposal. While a significant part of the science described here has developed from work included in the previous proposal, unification has enabled some exciting new projects. The present request is to update upgrade NMR facilities, now both antiquated and inadequate for specialist and routine analytical research. A shared (SPPS with Chemical Department) 500 MHz instrument (magnet JREI 2000-upgraded) has outdated (ca. 1990) and limiting console and probe electronics. SPPS¿s current 300 MHz, JREI 2000-upgraded, spectrometer requires a 24-place sample changer to speed routine sample throughput, especially at night, because of an increase in medicinal chemistry and drug delivery synthetic work (staff expansion by 5 NMR-user academics plus associated postgrads/postdocs in the past 3 years). The 300 MHz sample accessory will help with routine organic NMR, but not be enough in terms of daily capacity: an added 400 MHz NMR equipped for indirect detection and other nuclei is needed to deal with increased load/sample complexity. The 300 + 400 MHz spectrometers will be sited in a new-build SPPS NMR suite, and the 500 MHz in the Chemical Department. In 2005 SPPS fully relocates to new (at architect design stage) purpose-built labs (approximately 7000 m-squared, 12 million pounds) in a fully redesigned and internally refabricated multidisciplinary section of the Stopford Building, close to Medicine, Biological Sciences and Chemical Building. Projects include: New NMR tools for structural biology; Multi-domain proteins and complexes; Ultra-specificity in fluorescent genomics via target-assembled detectors; Nanoscale target-assembled transition metal-based luminescent probes; novel chemically functionalised Green Fluorescent Protein mutants; RNA-based NMR targets (artificial ribonucleases plus the IRES RNA element of EMCV picornavirus RNA); Chemical biology and rational design of lead compounds (including drugs and pro-drugs for hypoxic diseases, antiparasitics; research into potentially prebiotic chemistry, nucleic acid mimics; complex macrocyclics; synthesis of single enantiomers of amphetamine analogues for Parkinson¿s disease; ribosomal protein structures; dendrimers for novel drug delivery). Our specific objectives is to maintain cross-campus NMR capability at the level needed for international-quality research in these fields.