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HINT as putative phosphoramidase responsible of pro-tides activation: Molecular modelling studies [Abstract]

Congiatu, C., McGuigan, Christopher and Brancale, Andrea 2007. HINT as putative phosphoramidase responsible of pro-tides activation: Molecular modelling studies [Abstract]. Antiviral Research 74 (3) , A71. 10.1016/j.antiviral.2007.01.115

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Abstract

The ProTide approach was developed by McGuigan et al. as a method to improve the biological activity of poorly active nucleoside analogues by “kinase bypass” in which lipophilic nucleotide pro-drugs act as intracellular phosphate delivery motifs and achieve the generation of free nucleotides by nucleoside kinase-independent means. The activation of phosphoramidates is considered to be based upon two enzymatic cleavages: the hydrolysis of the amino acid ester moiety as the trigger of the process, and the Psingle bondN bond cleavage as the final step that would release the corresponding nucleoside analogue monophosphate. The latter step is carried out by an enzyme with phosphoramidase activity and it has been proposed that the protein responsible of the cleavage of the Psingle bondN bond belongs to the HINT family: adenosine monophosphoramidates AMP-NH2, AMP-N-ɛ-(N-α-acetyl lysine methyl ester) and AMP-para-nitroaniline were identified as rabbit Hint and yeast Hint1 substrates. Notably, AMP-N-alanine methyl ester was also reported as a substrate for the same enzymes, which might indicate their role in the activation of our phosphoramidates. We have recently reported some initial docking studies on a series BVDU phosphoramidate analogues in the human HINT-1 active site, which showed that indeed this enzyme could be able to bind and process the phosphoramidates. In the work presented here, we have extended the modelling simulations to different antiviral nucleoside analogues and examined their binding to HINT-1, as well as to the homology models of HINT-2 and HINT-3, with the aim of developing a predictive computational model which could be used in the design of more potent and selective phosphoramidate analogues (Fig. 1).

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Systems Immunity Research Institute (SIURI)
Additional Information: Abstract no. 107
Publisher: Elsevier
ISSN: 0166-3542
Last Modified: 18 Oct 2017 13:08
URI: http://orca-mwe.cf.ac.uk/id/eprint/6479

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