Talk Cancer

Question:

G’day Dave; Len: The compound is old. The models are old, the hype is new.   Do you mean that you know this drug from past press?   I can only hope that even some of these older drugs may find use now that a more solid core treatment is available.  IE some drugs that were only slightly effective in the past may be more useful on the buttress of HAART.  

The compound has been slowly developed over a long period. It has been in the literature and patent data bases for a few years now. It has just been a case of slow development. Len: It’s an RTI. We had models before of RT active site and some structural data, the CDC announced discovery is different;

Dave:   I thought that there was a body of work on the enzymology of RT but have never followed the subject into 3D.  

Search pubmed using the terms "reverse transcriptase and crystal structure". Any reverse transcriptase is important as they are structurally related, differing in subtle ways due to the bound metal ligand. Len: The ligand is actually bound, so the mode of binding is known. This dNTP is unrelated to the previous "new" drug. The important bit from the paper is as follows:

Dave:   I couldn’t find ligand in any of my dictionaries.  I did find other words with it’s latin root ‘binding’.  So the ligand must be the point at which the two molecules actually stick together.  

No, that’s the active site. A ligand is anything which binds to it to alter the catalytic rate without being substrate. In reverse transcriptase there is the protein with the following ligands: Mg/Mn++, RNA template (single stranded), dNTPs. Some ligands are important (metal ion and dNTP in this case) as they change the protein conformation and have direct implications in the binding mode. Dave:   There appears to be even more work needed on the model.  Billi Goldberg found an interesting chessnut the other day that may interest you.   It seems that there are larger possible mutation posibilities for this molecule that are viable.

Yes Billi has found a nice piece there. This highlights even more the poor choice RT is for inhibition, I do disagree with her statement about the immune system however. Have a day!                             |// Len…                     `_ _’/                 "Life is a comedy for the thinking man,                Life is a tragedy for the feeling man."                                   William Shakespeare                         .oooO                                   (   )   Oooo.                           _)    ) /  3D Centre for Drug Design &                                 (_/ Development. University of Queensland

Response:

G’day Dave;   So it must be a new non-nuke RTI.   Let us hope that it’s a good one!    Dave Let us hope it is THE one! Louis The compound is old. The models are old, the hype is new.

  Do you mean that you know this drug from past press?   I can only hope that even some of these older drugs may find use now that a more solid core treatment is available.  IE some drugs that were only slightly effective in the past may be more useful on the buttress of HAART.   – Hide quoted text — Show quoted text –    If it isn’t the drug against RT it may be just one of the next ones.    There was an interesting article in todays CDC Prevention news (formerly the dailys) that had some news about RT.   I though that this work had already been done but according to this new clip they have jut managed to map the functionality of RT… IE they have figured out the active sites of the molecule.   This may make other classes of drugs possible that interfear with it the way that the proteases inhibitors interfear with protease.    Here is that clipping:    Dave It’s an RTI. We had models before of RT active site and some structural data, the CDC announced discovery is different;

  I thought that there was a body of work on the enzymology of RT but have never followed the subject into 3D.   "Structure of a Covalently Trapped Catalytic Complex of HIV-1 Reverse Transcriptase: Implications for Drug Resistance" Science (11/27/98) Vol. 282, No. 5394, P. 1669; Huang, Huifang; Chopra, Rajiv; Verdine, Gregory L.; et al. The ligand is actually bound, so the mode of binding is known. This dNTP is unrelated to the previous "new" drug. The important bit from the paper is as follows:

  I couldn’t find ligand in any of my dictionaries.  I did find other words with it’s latin root ‘binding’.  So the ligand must be the point at which the two molecules actually stick together.   – Hide quoted text — Show quoted text -The researchers note that two broad conclusions can be drawn from the structure: point mutations that are sufficient for resistance are all in the neighborhood of the incoming nucleotide and that the mutation sites which confer resistance to the dideoxy class of RT inhibitors all impinge on the "front," while AZT resistance mutation sites impinge on the 3′-carbon pocket from the "rear."   A multinucleotide resistance mutation at position 151 lies in the middle of these positions, directly across the bound dNTP.  The authors conclude that "the clustering of mutations correlates well with cross resistance." What this means is they can see where the common mutations occur and feel they can explain mutations from a structural and sequence POV. This makes it possible to design an inhibitor to avoid resistance or to design inhibitors with unique resistance patterns, however since the the cluster is so puckered about the one critical or close to the one critical region, it is still a poor target for therapeutic intervention in my opinion. Nice piece of work though.

  There appears to be even more work needed on the model.  Billi Goldberg found an interesting chessnut the other day that may interest you.   It seems that there are larger possible mutation posibilities for this molecule that are viable. ====  quote on === Newsgroups: sci.med.aids Organization: unspecified Point mutations in the HIV RT gene were the first reason for the failure of the RT inhibitor antiviral drugs. In the 11/15/98 JCI, they have now found 6-basepair inserts in the HIV RT gene. Winters et al. (1998) (Merrigan’s group) state: "These results establish that inserts, like point mutations, are selected in vivo during antiretroviral therapy and provide resistance to multiple nucleoside analogs." Interesting how viruses can undergo so many gene changes and still function. Even more interesting is how the immune system continually evolves to adapt to such changes. Full article freely available at the Journal of Clinical Investigation website: http://www.jci.org/cgi/content/full/102/10/1769 Winters MA, Coolley KL, Girard YA, Levee DJ, Hamdan H, Shafer RW, Katzenstein DA, and Merigan TC. A 6-basepair insert in the reverse transcriptase gene of human immunodeficiency virus type 1