Biomedical subjects
Publications and source records attributed to A De Mesmaeker.
In this paper we summarize our efforts toward optimizing key reactions on the solid phase which tolerate a variety of functional groups. These groups were sequentially modified, allowing the production of novel and diverse compound libraries on the solid phase.
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A variant form of a group I ribozyme, optimized by in vitro evolution for its ability to catalyze magnesium-dependent phosphoester transfer reactions involving DNA substrates, also catalyzes the cleavage of an unactivated alkyl amide when that linkage is presented in the context of an oligodeoxynucleotide analog. Substrates containing an amide bond that joins either two DNA oligos, or a DNA oligo and a short peptide, are cleaved in a magnesium-dependent fashion to generate the expected products. The first-order rate constant, kcat, is 0.1 x 10(-5) min-1 to 1 x 10(-5) min-1 for the DNA-flanked substrates, which corresponds to a rate acceleration of more than 10(3) as compared with the uncatalyzed reaction.
In the past year major advances have been made in the design, synthesis and characterization of two classes of modified oligonucleotides. In the first class, the phosphodiester backbone of 2'-deoxyribo-oligonucleotides has been replaced in several different ways. The second group represents a completely different type of oligonucleotide modification in which the backbone and the 2'-deoxyribose moieties are replaced by amino acids. These advances present new possibilities for the pharmaceutical applications of modified oligonucleotides in antisense strategies.
The effect of the replacement of the natural phosphodiester linkage -C3'-O-PO2-O-CH2-C4'- in the DNA strand of RNA.DNA hybrid duplexes by either of the two amide linkages -C3'-CH2-CO-NH-CH2-C4'- or -C3'-CH2-NH-CO-CH2-C4' has been investigated by molecular mechanics (MM) and molecular dynamics (MD) simulations. Conformational analysis has been used to assess various low-energy conformers of the amide-modified backbones. MD simulations have been carried out to study the dynamic behavior of the modified duplexes. The modified RNA.DNA hybrid double helices kept a conservative base pairing scheme during the MD simulations. Although the general behavior has been found to be similar to that of the corresponding wild-type hybrid duplexes, some notable differences, especially regarding the sugar puckering in the amide-modified DNA strands, have been observed. The behavior of the RNA strands in the hybrid duplexes has not been affected by the modified DNA strands and is similar to that in wild-type RNA.DNA duplexes.
The backbone modification amide-3, in which -CH2-NH-CO-CH2- replaces -C5'H2-O5'-PO2-O3'-, is studied in the duplex d(G1-C2-G3-T4.T5-G6-C7-G8)*mr(C9-G10-C11-A12-A13-C14-G15+ ++-C16) where . indicates the backbone modification and mr indicates the 2'-OMe RNA strand. The majority of the exchangeable and non-exchangeable resonances have been assigned. The assignment procedure differs from standard methods. The methyl substituent of the 2'-OMe position of the RNA strand can be used as a tool in the interpretation. The duplex structure is a right-handed double helix. The sugar conformations of the 2'-OMe RNA strand are predominantly N-type and the 2'-OMe is positioned at the surface of the minor groove. In the complementary strand, only the sugar of residue T4 is found exclusively in N-type conformation. The incorporation of the amide modification does not effect very strongly the duplex structure. All bases are involved in Watson-Crick base pairs.
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