Sweet interactions with sugar moieties: From conformational analysis of saturated heterocycles to making drugs out of interfering RNAs

CARB 6

Muthiah Manoharan, mmanoharan@alnylam.com, Alnylam Pharmaceuticals, 300 Third St, Cambridge, MA 02142
This presentation will describe key evaluations of carbohydrate functionalities alone and as part of an oligonucleotide construct made over the past two decades. We will discuss (i) the determination of conformational free energy, for example, of the -CH2OH group at 2-position of pyranose sugars carried out in the laboratories of Ernest Eliel; (ii) delineation of DNA repair enzymatic pathways of abasic sites performed in the laboratory of John Gerlt; (iii) the structure-activity relationship of various 2'-modifications of furanose sugar in antisense oligonucleotides evaluated in the group of Dan Cook at Isis Pharmaceuticals and later in siRNAs by scientists at Alnylam Pharmaceuticals; and (iv) chemical modifications and conjugation chemistry of RNAs to improve cellular delivery of siRNAs and “antagomirs” now being evaluated at Alnylam.