Inhibition of reverse transcriptase

[Giovanni Maga]

In article <3pqidl$gas at mserv1.dl.ac.uk>, "Andrew, Tel. +396-91093434"
<WALLACE at IRBM.IT> wrote:


> 
>    I agree with you that theoretically, this should be an effective approach
> and ought to keep the virus "on the hop" as it were, with constantly changing
> selection pressures preventing the buildup of large virion numbers and thus
> improving the patient's chances, perhaps even eliminating the virus
> completely. One problem is that I don't think there are enough drugs with
> truly different modes of action available yet. We'll just have to keep on
> spending those research dollars until there are... 
> 

An interesting proposed approachis to use inhibitors targeted at the same
enzyme, but with different binding sites. It is not uncommon to find
cross-resistance to different nucleoside analogs (i.e. AZT and ddanalogs),
because they are targeted to the active site of RT and probably one
mutation can confere resistence to them. If the RT is challenged by
nucleoside and non-nucleosidfe inhibitors (for example AZT or ddI and TIBO
or Nevirapine), indipendent mutations in different parts of the same RT
molecule must occurr to give full resistence. This would take longer time
and maybe most of the mutated RT should become inactive or poorly active
due to the extensive changes. Combination of drugs with different molecular
targets should be helpful, but theoretically, the probability of developing
single mutations in different molecules (like RT and protease) colud be
less challenging for the virus. There is an example in the bacterial world:
resistence to pennicillins in some sp. involves independent mutations in
different PBPs. Of course bacteria undergo to a more extensive genetic
exchange between different sp. than viruses, thus increasing the
possibility of mutating, but HIV has on his side the high mutation rate. I
certainly agree with you about the necessity to develope new
*unconventional* inhibitors.
Just my 2 cents. G.Maga
maga at vetbio.unizh.ch