Gas station without pumps

2011 August 11

DRACO: broad-spectrum antiviral drugs

Filed under: Uncategorized — gasstationwithoutpumps @ 08:20
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In a recent article in PLoS ONE, Broad-Spectrum Antiviral Therapeutics, a group of MIT researchers introduced a new class of drugs that are the first broad-spectrum antivirals.

The DRACO molecules (for Double-stranded RNA (dsRNA) Activated Caspase Oligomerizer) are proteins with two domains: one domain recognizes long double-stranded RNA molecules, and the other domain induces apoptosis (cell death).  Different DRACO molecules can be made by changing how the dsRNA is detected and how apoptosis is induced.

Long dsRNA is a unique signature of most viral infections (even DNA viruses usually produce dsRNA, according to the authors).  Short double-stranded RNA is produced normally in healthy mammalian cells, but these dsRNA are only about 23 base pairs long, while viral dsRNA is part of the viral reproduction cycle and is 1000s of base pairs long.  So detecting long dsRNA is a pretty reliable indication of a viral infection.

Getting rid of a viral infection once it starts is difficult, and the approach used here is to kill off the cells that are infected before the virus manages to reproduce. Many natural defenses against viruses work this way also, and viruses have evolved various ways of interfering with the apoptosis pathway, to keep the cell alive long enough for the virus to reproduce.  The idea here is to trigger the apoptosis further along in the pathway than most viruses interfere.  This should work well, at least until the viruses evolve mechanisms that stop apoptosis through different mechanisms.  It is reasonable to hope that the viral evolution will be slower than the development of new DRACO molecules, since major new mechanisms would need to evolve, not just minor variants of existing ways of evading apoptosis.

One concern I have is that apoptosis-based therapies kill cells in which viral infection is detected, and may worsen the consequences of the viral infection if they kill off more cells than the viruses would have.  I believe the thought is that the cells would have been killed by the virus anyway, so killing the cell should not worsen the disease, and killing the cells before the virus can escape means that many fewer cells die.  This sounds good, and it seems to work well in cell cultures, but I’d still worry a little: do cells that have a minor viral infection that the natural cell defenses can handle still get killed?  Do cells that are difficult for the body to replace, like neural cells, get killed at a higher rate with DRACOs than without?  They tested for toxicity in uninfected cell cultures for several cell types, but not for neural cells and not for cultures with low-grade infections.

The other problem is that the DRACO molecules are not small molecule drugs, but large proteins.  That means that oral delivery is not likely—the drug is probably only going to be usable as an injection, and so will probably be used only for viral infections that are serious.  In a way, that’s a good thing, as it will slow down viral evolution of drug resistance (compared to over-the-counter drugs, which are greatly over used), but it does mean that the DRACO drugs will not be that useful against rhinoviruses and other “common cold” viruses, though that is mainly what the MIT people tested them with.

8 Comments »

  1. “do cells that have a minor viral infection that the natural cell defenses can handle still get killed?”

    I guess I’m not as up on immunology as I thought. Is there any natural defense against virally infected cells other than to kill those cells? I know there are viruses that don’t kill the cells they infect (i.e. herpes), but the only ones I know of are viruses that stay forever, because they keep a pool of cells around from which they can re-infect the rest of the host.

    IOW, my understanding of virus fighting is that “kill every virally infected cell” is pretty much the Holy Grail of virus fighting. No?

    As for usage, what’s the dosage routine? Given the number of people who get the flu shot every year to try to stay healthy, I would bet there will be a rather large pool of people willing to take one or two shots in order to stop a flu infection in its tracks. If it’s “one shot, and one day later you’re cured”, I think they’ll make a lot of money selling this to flu sufferers. If it’s “five shots, and you’ll be cured in a week”, then I think you’re looking at “serious infections only”.

    Comment by Greg Dougherty — 2011 August 11 @ 10:09 | Reply

    • I’m no expert on immunology either. I don’t know what mechanisms mammalian cells have to deal with viruses other than apoptosis, but I’m sure there are some. Perhaps I can find an immunologist to comment on this post.

      The DRACO approach is a long way from human trials, so no one knows what the dosage schedule would be like. They have gotten as far as mouse models, for which they used a single injection. But they sacrificed the mice a few days later, so there is no long-term safety information there.

      Comment by gasstationwithoutpumps — 2011 August 11 @ 10:42 | Reply

  2. […] DRACO: broad-spectrum antiviral drugs (gasstationwithoutpumps.wordpress.com) […]

    Pingback by MIT docs may have cured the common cold « Earl's View — 2011 August 11 @ 14:08 | Reply

  3. I teach Immunology and also taught virology for several years, so I can clarify a few points for you.

    Generally speaking the antiviral mechanisms include:

    Type I (Alpha & beta) Interferons
    Natural killer cells
    Virus-specific cytotoxic T cells
    Antibody-mediated mechanisms

    The type I interferons launch the anti-viral innate immune response. Type I interferons are produced in direct response to virus infection and promote an anti-viral environment in cells. Initiation of the type I interferon-driven anti-viral state is dependent upon the detection of viral pathogen associated molecular patterns (PAMPS) by germ line encoded pattern recognition receptors (PRR). Engagement of PRRs with PAMP ligands results in the orchestrated activation of numerous signalling pathways that culminate in the nuclear translocation of a number of transcription factors. Secreted type I interferons act in both an auto- and paracrine fashion, alerting the surrounding cells to the presence of pathogens. They bind to interferon receptors on the cell surface and initiate a signalling cascade resulting in the activation of over 300 interferon-stimulated genes in the target cell, including a ribonuclease that degrades virus genomes. In addition they enhance the immune response to virus infection by promoting an adaptive immune response.

    Natural killer cells are innate immune system cells that play an important role in defense against viruses. They operate via a combination of activating and inhibitory receptors to distinguish between normal and virally infected cells. Natural killer cells produce cytokines and cytotoxic granules that kill virally infected cells.

    Virus-specific cytotoxic T cells and antibodies produced by plasma cells represent the two adaptive immune mechanisms that eliminate virally infected cells, and in the case of antibodies, also neutralize free viral particles, thereby blocking their infectivity. However, the contribution of cytotoxic T cells and of antibody-mediated mechanisms depend on the virus. Neutralizing antibodies are sufficient to protect the host against most cytopathic viruses such as measles, mumps, rubella, yellow fever and influenza. Noncytopathic viruses and viruses that can integrate into the cellular genome such as retroviruses (e.g., HIV), require virus-specific cytotoxic T cells to completely clear the infected cells.

    Several more points must be made here:
    1. A vigorous immune response is not always adequate to successfully clear a viral infection. Some viral infections are readily cleared while other types of viruses cause a chronically infected state.
    2. In many virus infections the damage is caused not by virus infection per se but rather by the inflammatory component of the immune response and/or by destruction of virally infected cells by the immune system itself. This is a major argument for immunization against viruses that have the potential of infecting the brain.
    3. Some viruses, such as the members of the herpes virus family, establish latency, a state in which no viral genes are transcribed, thereby “flying under the radar” of the immune system.
    4. Many viruses have evolved mechanisms to modulate and evade immune responses. I will several below.

    Both RNA and DNA viruses have evolved mechanisms to skew immune responses or to induce immunosuppression. These include the following
    1. Molecules that abort interferon-induced apoptotic mechanisms
    2. Molecules that skew the cytokine environment such that it disfavors anti-viral immunity.
    3. Molecules that block some antibody-mediated mechanisms.
    4. Molecules that counter natural killer cell responses.
    5. Molecules that allow evasion of cytotoxic T cells.

    In conclusion, anti-viral immune mechanisms are very complex and viral mechanisms for evading these mechanisms are sophisticated. It therefore seems unlikely that a single strategy will be effective against all of the 400 or so viral pathogens that infect humans.

    Comment by Martha Zuniga — 2011 August 11 @ 19:10 | Reply

    • Thanks, Martha! That clears up a lot of my questions, and confirms some of my vague thoughts. I figured that retroviruses and other viruses that have latent states would not be cleared by DRACOs, and I suspected that killing off all virus-infected cells might be hazardous. Your points added weight to my rather vague thoughts, and brought out some more points that I had not even thought about.

      Comment by gasstationwithoutpumps — 2011 August 11 @ 19:22 | Reply

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