There was recent article in Nature Reviews Drug Discovery entitled “Small molecules against RNA targets attract big backers.” The article described several molecules that came out phenotypic screeening programs at Novartis, Merck, and Pfizer. These molecules target RNA instead of protein. “This was a huge surprise to us,” says RAjeev Sivasankaranm head of neurosciences group at Novartis. The group had been trying for years to figure out how a small molecule LMI070 works.
It should have been no surprise. RNA is turning out to be far more important than protein in cellular biology. I suspect that many of the molecules we currently think work through proteins will turn out to actually work through RNA. And many of the molecules where we have been unable to explain the mechanism of action (and there are many, including gold), will turn out to work via RNA.
Since we used to think protein was the most important class of target for drugs, we forced most of the molecules into that paradigm. Now that it’s becoming clear that this is not the case, our understanding of the drugs’ mechanism of action are being transformed.
One thought on “RNA as a Target? Heck Yeah.”
Life is said to have originated in the RNA world. We all know about the big 3 important RNAs for the cell, mRNA, ribosomal RNA and transfer RNA. But just like the water, sewer, power and subway systems under Manhattan, there is another world down there in the cell which doesn’t much get talked about. These are RNAs, whose primary (and possibly only) function is to interact with other RNAs.
Like TB a few years ago –The RNA world was forgotten but not gone.
Start with microRNAs (of which we have at least 1,500 as of 12/12). Their function is to bind to messenger RNA (mRNA) and inhibit translation of the mRNA into protein. The effects aren’t huge, but they are a more subtle control of protein expression, than the degree of transcription of the gene.
Then there are ceRNAs (competitive endogenous RNAs) which have a large number of binding sites for microRNAs — humans have a variety of them all with horrible acronyms — HULC, PTCSC3 etc. etc. They act as sponges for microRNAs keeping them bound and quiet.
Then there are circular RNAs. They’d been missed until recently, because typical RNA sequencing methods isolate only RNAs with characteristic tails, and a circular RNA doesn’t have any. One such is called CiRS7/CDR1) which contain 70 binding sites for one particular microRNA (miR-7). They are unlike to be trivial. They are derived from 15% of actively transcribed genes. They ‘can be’ 10 times as numerous as linear RNAs (like mRNA and everything else) — probably because they are hard to degrade . So some of them are certainly RNA sponges — but all of them?
The latest, and most interesting class are the nonCoding RNAs found in viruses. Some of them function to attack cellular microRNAs and help the virus survive. Herpesvirus saimiri a gamma-herpes virus establishes latency in the T lymphocytes of New World primates, by expressing 7 small nuclear uracil-rich nonCoding RNAs (called HSURs). They associate with some microRNAs, and rather than blocking their function act as chaperones . They HSURs also bind to some mRNAs inhibiting their function — they do this by helping miR-16 bind to their targets — so they are chaperones. So viral Sm-class RNAs may function as microRNA adaptors.
Do you think for one minute, that the cell isn’t doing something like this.
I have a tendency to think of RNAs as always binding to other RNAs by classic Watson Crick base pairing — this is wrong as a look at any transfer RNA structure will show. https://en.wikipedia.org/wiki/Transfer_RNA. Far more complicated structures may be involved, but we’ve barely started to look.
Then there are the pseudogenes, which may also have a function, which is to be transcribed and sop up microRNAs and other things — I’ve already written about this — https://luysii.wordpress.com/2010/07/14/junk-dna-that-isnt-and-why-chemistry-isnt-enough/. Breast cancer cells think one (PTEN1) is important enough to stop it from being transcribed, even though it can’t be translated into protein.
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