(a) Inhibit the translation to protein by physically blocking the RNA strand making it impossible for ribosomes to translate it
(b) Activate the enzyme RNase H that specifically targets DNA-RNA duplexes and only degrades the RNA strand.
A lot of people in the field believe that antisense can only work effectively with RNase H activation and I tend to agree. The cell is amazingly efficient at making RNA and translating it to protein so if you have to get stoichiometric amounts of antisense ON to RNA into the cell you are likely to have a problem. The beauty with RNase H activation is that the system is catalytic. In other words the antisense ON gets released after RNA degradation and moves on to the next victim. The problem is that you cannot use regular DNA for antisense purposes as it has a very short half life in serum (~15 minutes). So you have to devise an analogue that is stable in serum, has high affinity towards RNA and activates RNase H. Now obviously this is no easy feat so why bother? The (theoretical) advantages when compared to traditional protein targeting drugs are:
(a) Complete selectivity only for the intended target
(b) You can target anything involving RNA
(c) The chemistry is the same every time. You just have to figure out what the sequence of your target is and synthesise the required ON
(d) Getting drugs to market is rapid because drug development is significantly faster
Obviously, things are much more complicated than this. Antisense was the big thing in the 80s. It was going to cure everything within the next decade but the reality is that only one product has made it to market. It's an ON called Vitravene (ISIS Pharmaceuticals) that prevents AIDS patients from going blind by targeting cytomegalovirus retinitis. That said a lot of advances have been made and there are numerous antisense ON in late stage clinical trials. Anyway, after this super condensed course in antisense ON I think we are ready for the actual paper. I'll let you off the hook for now. The next post should be up in a couple of days. D!