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How Polyphenols Work, Perhaps?

No medicinal chemist, in my experience, is enthusiastic about polyphenol compounds. At least, not after their first experiences with them. These things are all over the natural product landscape, and many of them have biological activities, but (1) they’re beastly to try to develop into drugs, and (2) no one understands very well what their targets might be or what they’re doing to them.
That second part may finally be coming into the light. This paper in ACS Chemical Biology suggests that many of these compounds (our old friend resveratrol among them) may be working their way into the bilayers of cell membranes and thus affecting the activity of membrane-bound proteins. If that’s true, then these compounds don’t have “targets” in the usual sense of the word. They have a mechanism, but it’s a broad one and likely to do all kinds of things in different cells under different conditions. We’ll see if this hypothesis pans out, but it looks reasonable (and fits a lot of the hard-to-categorize facts).

14 comments on “How Polyphenols Work, Perhaps?”

  1. Vladimir Chupakhin says:

    Sorry! But what surprised you? that compounds interact with membranes?

  2. MDACC GS says:

    Someone aught to tell GSK, if any of their employees are clever enough they could use this insight to prolong their IP protection.

  3. Pharmacologists (and by association med chemists) are almost all protein supremacists, even though the membrane activity of many bioactive small molecules, including psychoactives, has been appreciated for well over a hundred years. (Overton-Meyer, anyone?)
    The big open question to my mind revolves around structural determinants of drug-membrane specificity. Except for membranologists, people conceptualize (and draw ad nauseam) lipid bilayers as homogenous structures of cartoon-like simplicity and little potential for specificity. But that view is clearly not supported by reality.
    I’m hopeful more pharmacologists will remove their protein googles, but I’m not optimistic anything will change in the short-term..

  4. anon says:

    other posters:
    please take more time in thinking before responding.
    @1: derek’s claim is clearly not that “shockingly hydrophobic molecules like hydrophobic environment” its more that many people are claiming that they are protein specific mechanisms and here is “evidence” pointing to what many people think is much more likely.
    @3: takes a lotta balls to really fabricate such an outrageous straw man on lipid biophysics perception around the science world. feel free to point out how polyphenols are carrying out a specific drug effect using your supposed membrane-drug interaction.

  5. Anonymous says:

    Insane in the brain. Insane in the membrane.

  6. Dick Thomas says:

    I wish I had a dollar for every time I tried to talk a Team Leader down from a highly potent “hit” only to try to explain that (poly-)-catechols tend to do such things and they are not really good starting points for our disease target. I cannot begin to explain why these (many) compounds were in the screening set, but there they were and they caused me, as a chemist, a lot of heartache since they kept lighting up the screening assays and I took the heat for “killing our best leads”.
    I know that many have taken the path to develop similar structures and that some specific examples may well have some potential. But….. and, it is a big but(t), given my druthers, I would avoid poly-phenols in deference to other leads with better potential for eventual development.

  7. Mfernflower says:

    Fucking polyphenols, HOW DO THEY WORK 😀

  8. Lane Simonian says:

    Several studies suggest that polyphenols inhibit tyrosine phosphorylation. Tyrosine phosphorylation can lead to cell survival (via the phosphatidylinositol 3-kinase/Akt pathway) or cell death (via protein kinase C and p38 Mapk). Thus the recommendation of a diet high in vegetables and fruits to reduce the risk of cancer and a Mediterranean diet high in polyphenols to reduce the risk of Alzheimer’s disease.
    Depending on the circumstances, polyphenols can act as antioxidants or oxidants. Thus, the recommendation of a Mediterranean diet to extend life for Alzheimer’s patients and intravenous injections of vitamin C to kill cancer cells.

  9. David Borhani says:

    Isn’t this a case of selection bias?
    In other words, what if one ran the same experiments with a different set of compounds (say, aromatic amines), of similar charge/logP as the polyphenols? Surely many of the amines would exhibit effects on membrane protein activity when tested at concentrations of 10-50 micromolar?

  10. MoBio says:

    With regard to capsaicin the data are misleading (although I don’t doubt the data presented). Capsaicin has nM affinity for activating TRPV1 channels (Neurosci. Lett., 370 (1): 55-60) and in the paper they show effects in the 10’s of uM level.
    Undoubtedly casaicin has non-specific effects at these exceedingly high concentrations though there is now little doubt that it’s actions on taste and so-on are mediated via direct interactions with TRPV1.

  11. I wasn’t mean to be rude.
    My point is – many compounds do interact with membranes. In case of polyphenols it is mechanism, it is targets and it is a formation of aggregates of compounds themselves. Not only the mechanistic effect on membrane properties.

  12. Anonymous says:

    @4: Be sure I thought properly. The original study is interesting, but did not show drastically different results from what was already known for many decades. Mechanism of some antibiotics, most detergents are based on this.
    My gut filling just tells me that those compounds will not stay in membrane for a long time. Lipid environment will not keep them for too long – it should be very fast exchange. Search gave only this article for artificial membrane
    this gave a lot of research in 80s and 90s

  13. Lane Simonian says:

    Vladimir, your point is well made and well-taken. How effectively polyphenols reach and alter their targets is another matter, but their potential ability to do so in well-documented.

  14. Lane Simonian says:

    Here is a good article on some of the pathways and targets that polyphenols may effect.
    Effects of tea polyphenols on signal transduction pathways
    related to cancer chemoprevention
    Zhe Hou, Joshua D. Lambert, Khew-Voon Chin, Chung S. Yang∗
    Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers
    University, 164 Frelinghuysen Road, Piscataway, NJ 08854 8020, USA
    Received 28 April 2004; received in revised form 9 June 2004; accepted 10 June 2004
    The inhibition of carcinogenesis by tea and tea polyphenols has been demonstrated in different animal models by many investigators. The mechanisms of this inhibitory activity have also been investigated extensively, mostly in cell culture systems, but no clear conclusion can be reached concerning the cancer preventive mechanisms in vivo. In this article, we reviewed the possible mechanisms, which include the inhibition of specific protein kinase activities, blocking receptor-mediated functions,
    and inhibition of proteases. These events may lead to cell cycle regulation, growth inhibition, enhanced apoptosis, inhibition of angiogenesis, and inhibition of invasion and metastases. The possible complications of translating results obtained in cell culture studies to animals and humans are discussed. It is likely that multiple signal transduction pathways are involved in
    the inhibition of carcinogenesis by tea constituents. The relative importance of these pathways needs to be determined in vivo.

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