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Molecular probes are useful for both studying and controlling the functions of enzymes and other proteins. The most useful probes have high affinity for their target, along with small size and resistance to degradation. Here, we report on new surrogates for nucleic acids that fulfill these criteria. | 1FEBS Journal Functional and structural analyses of N-acylsulfonamide-linked dinucleoside inhibitors of RNase A Nethaji Thiyagarajan1 Bryan D. Smith2 Ronald T. Raines2 3 and K. Ravi Acharya1 1 Department of Biology and Biochemistry University of Bath UK 2 Department of Biochemistry University of Wisconsin-Madison USA 3 Department of Chemistry University of Wisconsin-Madison USA Keywords crystal structure N-acylsulfonamide-linked dinucleoside inhibitors RNase A Correspondence K. R. Acharya Department of Biology and Biochemistry University of Bath Claverton Down Bath BA2 7AY UK Fax 44 1225-386779 Tel 44 1225-386238 E-mail bsskra@bath.ac.uk R. T. Raines Department of Biochemistry University of Wisconsin-Madison 433 Babcock Drive Madison WI 53706-1544 USA Fax 1 608 890 2583 Tel 1 608 262 8588 E-mail rtraines@wisc.edu Present address Deciphera Pharmaceuticals LLC 643 Massachusetts Street Suite 200 Lawrence KS 66044-2265 USA Re-use of this article is permitted in accordance with the Terms and Conditions set out at http wileyonlinelibrary.com onlineopen OnlineOpen_Terms Received 17 September 2010 revised 29 November 2010 accepted 1 December 2010 Molecular probes are useful for both studying and controlling the functions of enzymes and other proteins. The most useful probes have high affinity for their target along with small size and resistance to degradation. Here we report on new surrogates for nucleic acids that fulfill these criteria. Isosteres in which phosphoryl R-O-P O2_ -O-R groups are replaced with N-acylsulfonamidyl R-C O -N -S O2 -R or sulfonimidyl R-S O2 -N -S O2 -R groups increase the number of nonbridging oxygens from two phosphoryl to three N-acylsulfonamidyl or four sulfonimidyl . Six such isosteres were found to be more potent inhibitors of catalysis by bovine pancreatic RNase A than are parent compounds containing phosphoryl groups. The atomic structures of two RNase A-N-acylsulfonamide complexes were determined at high resolution by X-ray .
