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ViroPharma Incorporated Message Board

  • You seem to have some background in the sciences. The investor day info on Maribavir was certainly interesting. What might explain efficacy in treating CMV but not in preventing it?

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    • nuhawk bro... i am just a surfah... what tiny knowledge i have in the sciences, i get from reading,..

      whiile treating implies a less potent drug I think maribavir can be used for preventing CMV... the management just lowered its aim- this strategic move got it an orphan drug designation with the hope that it will get to market rather than not at all... all imho.

      aloha,
      kamoa

    • Nuhaw, the following was taken from a scientific paper. It might not make sense at first but I will explain below:
      "The UL97 gene (full length of this gene is 2124 nt, encoding the protein of 707 aa) encodes the viral phosphotransferase. It shows important functions in DNA synthesis, encapsidation, and nucleocytoplasmic capsid export,8–10 which have important roles in the virus’ reproduction ability. Therefore, only a low degree of amino acid variations are detected in it, which are often associated with drug resistance.11 However, synonymous polymorphism in different UL97 sequences has been observed more easily than non-synonymous mutations. Traditionally, synonymous mutations are always thought to be insignificant since there are no changes in the amino acids. However, some exciting findings, published recently in top journals,12,13 suggest that synonymous mutations in exons or non-exons might affect the function of a protein by changing several biological behaviors, such as RNA processing mode after transcription, the speed of protein translation, and sequent protein folding. Any change in the aspects described above would influence the biological function of this protein and the virus. Therefore, the proposed hypothesis is that synonymous mutations are smart and adaptive rather than stochastic and meaningless, especially in these important and conservative genes like the UL97 gene. In this paper, the polymorphisms of the UL97 gene, especially the synonymous mutations, were analyzed in different populations from Ruijin Hospital in Shanghai."

      What this is saying is that Maribavir does its thing by binding the UL97 protein and preventing viral replication. However, the gene that encodes UL97 protein (kinase) is highly polymorphic among CMV isolates. In other words, the gene sequences that eventually synthesize the UL97 proteins are not the same in all CMV isolates. Also, in other papers, it is very possible that a single infection of CMV may actually contain multiple isolates of the virus. The work described above also suggests that even though the changes in the gene sequence of the UL97 may not necessarily end up in changes in the protein sequence, they nonetheless can control the way the protein is synthesized (simply put). So what does it all mean...or should I say what does it all imply. Well, one very strong possibility is that varibility in the trials could relate to variations in the population dynamics of the virus i.e. the structure of the virus in one location/hospital might be slightly different than the structure of the CMV virus in another hospital/location. Also, the infections can and often do contain mixtures rather than be a pure strains of virus. The problem with extrapolating the clinical studies from "test tube" studies is that cultured viruses are more likely to be homogeneous than heterogeneous. So when it gets out to the real world, Maribavir maybe working on some strains but not others. In another scientific paper, the authors stated, "The full-length UL97 gene sequence analysis from 4 laboratory strains and 35 clinical samples from patients who had not received any previous anti-CMV treatment was performed. At the nucleotide level, the interstrain identity was 98%. At the amino acid level, however, ten natural polymorphisms never previously described were identified." What this means is that in other instances it was indeed found that the UL97 protein can and does exhibit differences among strains. What is not known is whether or not this can account for variability in the effectiveness of the drug. I suspect there is or at least can be a relationship between the two.

      Zing

      • 1 Reply to zing21042
      • nice to see a post with useful info.
        i would add that not only could this make maribavir more effective with certain strains or class of patients it could help vphm develope isomers or slight changes to maribavir structure that would be effective against more strains etc. or like augmentin which uses clavulantic acid and amoxil.
        the clavulantic(spell?) acid decreases an enzyme the bacteria uses to defeat the amoxil before it gets to the bacteria.
        so maybe a second drug or enzyme could be added to maribavir to incr. effectiveness against broad strain of cmv.
        if nothing else it could help in future treatment of cmv by understanding the virus better

        Sentiment: Hold

 
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