A Hitchhiker's guide to antisense and nonantisense biochemical pathways

Abstract

Antisense pharmaceutical research has sought to provide drugs that would yield effective therapies for disAntisense pharmaceutical research has sought to strategieases resulting from the production of deleterious pro-cally design drugs that would predictably yield safe and effecteins. The original concept was straightforward: tive therapies. It is now clear that a broad knowledge of nueliminate production of unwanted proteins, such as on-cleic acid biochemistry will be needed to attain this goal and cogenic proteins, by blocking the function of their other related objectives. As originally conceived, antisense mRNAs; and block their mRNAs by adding ''antisense'' strategies were to offer a general and rational approach for nucleic acids that bind them through complementary designing treatments for all diseases resulting from the probase pairing. However, it has proven difficult to develop duction of deleterious proteins, such as viral, oncogenic, cytoclinically useful antisense strategies. Conventional anti-toxic, misfolded, or overly abundant proteins (including pepsense nucleic acids are large, highly charged, complex tide hormones). Figure 1 illustrates one type of antisense molecules that interact with a wide variety of unin-approach. In this model, the therapeutic molecule is an antitended cellular and microbial components, often caus-sense DNA oligonucleotide. It is composed of sequences coming ''nonantisense effects.'' It is now clear that a broad plementary to its target, a messenger (mRNA). The mRNA knowledge of nucleic acid biochemistry will be needed contains genetic information in the functional, or sense, orito optimize antisense molecules for use in patients. The entation. In the ideal strategy, binding of the antisense oligoefficacy of naturally occurring antisense molecules and nucleotide inactivates the intended mRNA and prevents its the success of antisense agricultural strategies prove translation into protein, while leaving all other RNAs unafthat antisense approaches can be powerful and specific. fected.5 Antisense strategies are based on biochemical experiPharmaceutical antisense research can be expected to ments showing 1) that proteins are translated from specific yield many valuable products once sufficient informa-RNAs; 2) that once the sequence of an RNA is known, it is tion about antisense mechanisms has been gathered and possible to design an antisense molecule that will bind to it applied. This article explains the biochemical events through complementary Watson-Crick base pairs; and 3) that that give rise to both antisense and nonantisense effects by manipulating conditions in vitro, it is possible to obtain and provides guidelines for designing and evaluating sequence-specific binding, albeit under conditions that are antisense experiments. (HEPATOLOGY 1996;24:1517-1529.) often far outside the physiological range.Several factors make it difficult to develop clinical applications of the classical antisense model presented in Fig. 1. PREAMBLEFirst, conventional antisense nucleic acid...

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