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Bioorg Med Chem Lett. 2014 May 15;24(10):2346-52. doi: 10.1016/j.bmcl.2014.03.064. Epub 2014 Mar 27.

Syntheses of stable, synthetic diadenosine polyphosphate analogues using recombinant histidine-tagged lysyl tRNA synthetase (LysU).

Author information

1
Imperial College Genetic Therapies Centre, Department of Chemistry, Imperial College London, Flowers Building, Armstrong Road, London SW7 2AZ, UK; Institute of Pharmaceutical Science, King's College London, Franklin-Wilkins Building, Waterloo Campus, 150 Stamford Street, London SE1 9NH, UK.
2
Imperial College Genetic Therapies Centre, Department of Chemistry, Imperial College London, Flowers Building, Armstrong Road, London SW7 2AZ, UK; Organic-I Division, Indian Institute of Chemical Technology, Habsigida, Hyderabad, India.
3
Organic-I Division, Indian Institute of Chemical Technology, Habsigida, Hyderabad, India.
4
Imperial College Genetic Therapies Centre, Department of Chemistry, Imperial College London, Flowers Building, Armstrong Road, London SW7 2AZ, UK; Institute of Pharmaceutical Science, King's College London, Franklin-Wilkins Building, Waterloo Campus, 150 Stamford Street, London SE1 9NH, UK. Electronic address: a.miller07@btinternet.com.

Abstract

Recombinant Escherichia coli lysyl-tRNA synthase (LysU) has been previously utilised in the production of stabile, synthetic diadenosine polyphosphate (ApnA) analogues. Here we report on the extended use of a new recombinant histidine residue-tagged LysU as a tool for highly controlled phosphatephosphate bond formation between nucleotides, avoiding the need for complex protecting group chemistries. Resulting high yielding tandem LysU-based biosynthetic-synthetic/synthetic-biosynthetic strategies emerge for the preparation of varieties of ApnA analogues directly from inexpensive natural nucleotides and nucleosides. Analogues so formed make a useful small library with which to probe ApnA activities in vitro and in vivo leading to the discovery of new, potentially potent biopharmaceuticals active against chronic pain and other chronic, high-burden disease states.

KEYWORDS:

Analogues; Biosynthesis; Diadenosine polyphosphate; Dinucleoside polyphosphates; Lysyl tRNA synthetase (LysU)

PMID:
24736113
DOI:
10.1016/j.bmcl.2014.03.064
[Indexed for MEDLINE]

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