Replies to post #94844 on Biotech Values

[DewDiligence]

I would think a boutique drug-discovery outfit such as IDIX could do each of these tasks except #1, which requires a comprehensive compound library.

At some point, we ought to see some discussion of what NS5A does for the HCV virus. Was this addressed in the article you read? In any case, I’d be interested in reading the article you read about BMS-790052. T.i.a. for a link, email, or any other reference you may have.

[iwfal]

NS5A inhibitors

They then analyzed where the HCV had mutated so as to become resistant to both these compounds, and this analysis together with the structure of the two compounds revealed that NS5A was their mutual target.

What am I missing... ? I can see how this would isolate a part of the hcv genome that evolves resistance to multiple drugs - but I don't see how this leads ipso facto to a drug that targets the part of the genome that can't change (and thus would be a good target for a drug).

PS I read the abstract you provided and it seems to imply that they found a drug that has as its target a part of NS5A that doesn't change - but it doesn't really describe how they isolated it. Perhaps I'll have to splurge for the article - but since it is a little outside of my mainstream interest I am hoping I can be cheap -g-.

[poorgradstudent]

HepC / NS5A paper:

>3. They then did some SAR analysis which enabled them to find a much more potent compound to which the above resistant cell lines were also resistant.

4. They then analyzed where the HCV had mutated so as to become resistant to both these compounds, and this analysis together with the structure of the two compounds revealed that NS5A was their mutual target.
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From my reading, you're accurate with #3 but out of sequence. They found one parent compound (BMS 858), and then used it as a basis for additional chemical modifications to improve bioavailability and symmetry (reasoned from a referenced publication). This compound following structural refinement became BMS-790052. It is actually the final form of the compound, and the one that they used to make resistant lines.

For #4, they found mutations that conferred resistance to BMS-790052 (judged as allowing growth at 20x normal EC50), and then observed that for most of those resistant phenotypes, the new EC50 was still below the plasma levels of the drug in vivo. Also, in many cases, they observed that the discovered mutations reduced the fitness of the virus to the point where they don't really proliferate in vivo with those mutations anyways.

It's also my understanding from reading the paper that they figured out rather early that NS5a was the target. The surprise was as you suggest: NS5A doesn't really have a catalytic activity and is therefore not a classic target for "inhibition", but that it appears the inhibitor that they've designed and characterized interrupts dimer formation by NS5A that is crucial to its role in RNA replication. In that sense, they used the NS5A point mutations that conferred resistance to BMS-790052 as a means to map where the inhibitor was binding (ie. figure out its mode of action) rather than using them as clues to reformulate the compound into a more potent form.

[genisi]

That of course came as a surprise to them, as NS5A had no enzymatic activity and an unknown function.

Not really surprising from a genetic/evolutionary point of view as small RNA viruses usually do not waste their time encoding something that is not important to at least some aspect of their replication cycle.