Inhibition of reverse transcriptase

[TengLeong Chew]

In article <3pikq7$hsh at mserv1.dl.ac.uk>,
Andrew, Tel. +396-91093434 <WALLACE at IRBM.IT> wrote:
>
>   Yes indeed, it is possible to find compounds which inhibit reverse
>transcriptase and in particular much effort (and money) has been expended over
>the last several years by various organizations and individuals to find
>inhibitors of the reverse transcriptase of HIV. (I presume you were thinking
>along these lines?) Many of these compounds function very well in the test
>tube but beyond that there are many difficulties in using these on people,
>usually because of one or more of the following problems:
>
>1) The compound is too toxic to be used safely in treating people with HIV.
>
>2) Treatment with even safe and "test tube effective" compounds results in the
>rapid appearance of mutant HIV strains which are resistant to the drug.

	One important point to note is that most, if not all, of the drugs
designed to combat HIV reverse transcriptase are substrate analogs, for
example: AZT, ddI, ddC etc. They are basically DNA building blocks with
screwed up links, which when incorporated by the RT, terminate the
elongation process. 

	As far as I know, nobody at this juncture has succesfully
generated a drug that can crosslink or covalently destroy the RT activity.
And that is thus far the best hope to curb the high mutation and
mismatching rate intrinsic of all RTs.
	
>   This appears to apply also to compounds which are active against other
>viral enzymes, such as the HIV protease. For an example of this phenomenon
>there was a recent article in Nature where HIV-infected patients were treated
>with a variety of different protease inhibitors. In all cases drug-resistant
>strains of the virus eventually emerged which were not only resistant to the
>original drug used on the patient but were also cross-resistant to the other
>anti-protease drugs tested.
>
>   They are now hoping that treatment with combinations of drugs having
>different activities will be effective. I hope so.
>
	Combinatorial drug therapy has so far proved ineffective. The
biological pressure imposed by the drugs is not strong enough to wipe out
the viruses, but has forced them to adapt, just like many tumor cells
becoming multidrug resistant when cancers reoccur after chemotherapies put
them under remission.


 - T. L. Chew


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