INHIBITION OF (CYTOSINE C5)-METHYLTRANSFERASE BY OLIGONUCLEOTIDES CONTAINING FLEXIBLE (CYCLOPENTANE) AND CONFORMATIONALLY CONSTRAINED (BICYCLO[3.1.0]HEXANE) ABASIC SITES

Victor E. Marquez

Peiyuan Wang

Marc C. Nicklaus

Martin Maier ISIS Pharmaceuticals, Inc., 2292 Faraday Ave., Carslbad, California, 92008, U.S.A.

Muthiah Manoharan ISIS Pharmaceuticals, Inc., 2292 Faraday Ave., Carslbad, California, 92008, U.S.A.

Judith K. Christman Department of Biochemistry and Molecular Biology and UNMC/Eppley Cancer Center, University of Nebraska Medical Center, 600 South 42nd St., Nebraska, 68198, U.S.A.

Nilesh K. Banavali Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, 21201, U.S.A.

Alexander D. Mackerell Jr. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, 21201, U.S.A.

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Abstract

Pseudorotationally locked sugar analogues based on bicyclo[3.1.0]-hexane templates were placed in DNA duplexes as abasic target sites in the M.HhaI recognition sequence. The binding affinity of the enzyme increases when the abasic site is constrained to the South conformation and decreases when it is constrained to the North conformation. A structural understanding of these differences is provided.

Acknowledgments

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INHIBITION OF (CYTOSINE C5)-METHYLTRANSFERASE BY OLIGONUCLEOTIDES CONTAINING FLEXIBLE (CYCLOPENTANE) AND CONFORMATIONALLY CONSTRAINED (BICYCLO[3.1.0]HEXANE) ABASIC SITES

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INHIBITION OF (CYTOSINE C5)-METHYLTRANSFERASE BY OLIGONUCLEOTIDES CONTAINING FLEXIBLE (CYCLOPENTANE) AND CONFORMATIONALLY CONSTRAINED (BICYCLO[3.1.0]HEXANE) ABASIC SITES

Abstract

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