期刊
ACCOUNTS OF CHEMICAL RESEARCH
卷 53, 期 10, 页码 2152-2166出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.accounts.0c00078
关键词
-
资金
- National Institutes of Health [GM 25684, GM 21120]
Chemically modified oligonucleotides are being developed as a new class of medicines for curing conditions that previously remained untreatable. Three primary classes of therapeutic oligonudeotides are single-stranded antisense oligonudeotides (ASOs), double stranded small interfering RNAs (siRNAs), and oligonucleotides that induce exon skipping. Recently, ASOs, siRNAs, and exon skipping oligonudeotides have been approved for patients with unmet medical needs, and many other candidates are being tested in late stage clinical trials. In coming years, therapeutic oligonudeotides may match the promise of small molecules and antibodies. Interestingly, in the 1980s when we developed chemical methods for synthesizing oligonudeotides, no one would have imagined that these highly charged macromolecules could become future medicines. Indeed, the anionic nature and poor metabolic stability of the natural phosphodiester backbone provided a major challenge for the use of oligonudeotides as therapeutic drugs. Thus, chemical modifications of oligonudeotides were essential in order to improve their pharmacokinetic properties. Keeping this view in mind, my laboratory has developed a series of novel oligonudeotides where one or both nonbridging oxygens in the phosphodiester backbone are replaced with an atom or molecule that introduces molecular properties that enhance biological activity. We followed two complementary approaches. One was the use of phosphoramidites that could act directly as synthons for the solid phase synthesis of oligonucleotide analogues. This approach sometimes was not feasible due to instability of various synthons toward the reagents used during synthesis of oligonudeotides. Therefore, using a complementary approach, we developed phosphoramidite synthons that can be incorporated into oligonudeotides with minimum changes in the solid phase DNA synthesis protocols but contain a handle for generating appropriate analogues postsynthetically. This Account summarizes our efforts toward preparing these types of analogues over the past three decades and discusses synthesis and properties of backbone modified oligonudeotides that originated from the Caruthers' laboratory. For example, by replacing one of the internudeotide oxygens with an acetate group, we obtained so-called phosphonoacetate oligonudeotides that were stable to nucleases and, when delivered as esters, entered into cells unaided. Alternatively oligonudeotides bearing borane phosphonate linkages were found to be RNase H active and compatible with the endogenous RNA induced silencing complex (RISC). Oligonudeotides containing an alkyne group directly linked to phosphorus in the backbone were prepared as well and used to attach molecules such as amino acids and peptides.
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