DRACO broad-spectrum antiviral

[hrandani]

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0022572

I think this is a very cool mechanism but as I was reading the paper I sort of hit a brick wall in understanding how it works.

They assert that all virus create a double stranded RNA molecule at some point during replication. I've spent about two hours going over all my textbooks, wikipedia, random google searches, you name it, and cannot figure out where this dsRNA molecule occurs other than in two specific situations, when RNA dependent RNA polymerase creates a +RNA from a -RNA for -RNA virus, and when mRNA uses a hairpin mechanism to self-splice introns. However, if self-splicing was the trigger it seems like that would cause all human cells to undergo apoptosis.

If anyone could expound on this point and help me understand what universal process exists that all virus create a dsRNA molecule I would really appreciate it. They cite a virology textbook. I feel like I'm missing something really basic.

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[VoiceofReason]

you can't handle the truth

 

[FunnyCurrent]

you can't handle the truth

 

[Lbgem]

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0022572

I think this is a very cool mechanism but as I was reading the paper I sort of hit a brick wall in understanding how it works.

They assert that all virus create a double stranded RNA molecule at some point during replication. I've spent about two hours going over all my textbooks, wikipedia, random google searches, you name it, and cannot figure out where this dsRNA molecule occurs other than in two specific situations, when RNA dependent RNA polymerase creates a +RNA from a -RNA for -RNA virus, and when mRNA uses a hairpin mechanism to self-splice introns. However, if self-splicing was the trigger it seems like that would cause all human cells to undergo apoptosis.

If anyone could expound on this point and help me understand what universal process exists that all virus create a dsRNA molecule I would really appreciate it. They cite a virology textbook. I feel like I'm missing something really basic.

I saw/skimmed over the abstract that paper on Friday and I'll read over it tomorrow to see exactly. To answer your question - it's your first guess. dsRNA is temporarily created by the polymerase. Also keep in mind some/most? viruses don't have introns, and I think that paper said their mechanism could be applied to a large range of viruses.

 

[Elbowstoopointy]

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0022572

I think this is a very cool mechanism but as I was reading the paper I sort of hit a brick wall in understanding how it works.

They assert that all virus create a double stranded RNA molecule at some point during replication. I've spent about two hours going over all my textbooks, wikipedia, random google searches, you name it, and cannot figure out where this dsRNA molecule occurs other than in two specific situations, when RNA dependent RNA polymerase creates a +RNA from a -RNA for -RNA virus, and when mRNA uses a hairpin mechanism to self-splice introns. However, if self-splicing was the trigger it seems like that would cause all human cells to undergo apoptosis.

If anyone could expound on this point and help me understand what universal process exists that all virus create a dsRNA molecule I would really appreciate it. They cite a virology textbook. I feel like I'm missing something really basic.

Will it cure the herp? (no herp)

 

[Elbowstoopointy]

you can't handle the truth

hahaha

 

[celkon]

+RNA --> -RNA --> +RNA
-RNA --> +RNA --> -RNA

only times i can think of when there would be a double stranded RNA made, but both mechanisms use RNA dep. RNA pol., dont think they are annealed for very long if ever, maybe randomly?

 

[Lbgem]

They assert that all virus create a double stranded RNA molecule at some point during replication. I've spent about two hours going over all my textbooks, wikipedia, random google searches, you name it, and cannot figure out where this dsRNA molecule occurs other than in two specific situations, when RNA dependent RNA polymerase creates a +RNA from a -RNA for -RNA virus

Here - I consider it something like DNA replication where 3' to 5' creates a complimentary strand 5' to 3' that is bound to it while being made during replication. http://www.nature.com/nrmicro/journal/v5/n2/fig_tab/nrmicro1597_F2.html It has an arrow showing neg. strand being made from pos., but you can imagine there's a polymerase there binding to the template while creating the complimentary copy.

Also, the paper tells you when it's formed: "Most viruses have double- or single-stranded RNA (ssRNA) genomes and produce long dsRNA helices during transcription and replication; the remainder of viruses have DNA genomes and typically produce long dsRNA via symmetrical transcription." And if you look at the source where they get it from: "Knipe DM, Howley PM, editors. (2006) Fields Virology, 5th ed. Philadelphia: Lippincott Williams & Wilkins. " Makes me wish I didn't sell my Fields... But if you have one lying around, you can find it in there. Btw, Fields is pretty much the bible of Virology, it has the most minute details you'd ever want to know, and the chapters are usually written by the field experts.

So yes, it was your first guess .

 

[Lbgem]

Will it cure the herp? (no herp)

Hm I think this system might have a problem with it. According to the paper, there's no mention of it so I gather they haven't tried it. But more so, it's a ds DNA virus that goes latent by hiding in the host chromosome. Which means no dsRNA produced, which means no way for this DRACO system to detect/eliminate it. I can see it working for the lytic phase of the virus (i.e. helping with active infections/break outs) but not for the latent.

 

[Elbowstoopointy]

Hm I think this system might have a problem with it. According to the paper, there's no mention of it so I gather they haven't tried it. But more so, it's a ds DNA virus that goes latent by hiding in the host chromosome. Which means no dsRNA produced, which means no way for this DRACO system to detect/eliminate it. I can see it working for the lytic phase of the virus (i.e. helping with active infections/break outs) but not for the latent.

Ok...so I still have to be paranoid every time I hook up with a girl since 1 in 4 have it

 

[Lbgem]

Ok...so I still have to be paranoid every time I hook up with a girl since 1 in 4 have it

Yup sorry .

 

[hrandani]

Thanks again. I read that sentence and wanted more details because it really just did not compute. I went over several micro books and the process of dsRNA formation is never mentioned, either implicitly or explicitly.

I guess I just didn't catch onto this symmetrical transcription thing. I've definitely never heard of that until today. Looks like the herpes virus does produce dsRNA via symmetrical transcription though:

http://www.nature.com/nature/journal/v254/n5502/abs/254719a0.html

Paper came out in 1975...

 

[DoctwoB]

All RNA viruses must produce at least a transient dsRNA intermediate. In replicating + or - RNA, you have to produce the opposite sense RNA, thus forming a dsRNA molecule. Also remember that there doesn't have to be an entire dsRNA genome. Any partially annealed dsRNA is enough for a dsRNA binding protein to bind. Many endogenous human anti-viral defenses already act to target dsRNA e.g. PKR induced inhibition of translation.

This theoretical broad-spectrum anti-viral links the endogenous dsRNA binding proteins to apoptosis inducing machinery. Cool mechanism, but color me unexcited until we see some human trials. Wayyy too many in vitro and mouse studies don't pan out then turn into usable drugs. More often then not, the new drug is also an incremental improvement, not a complete game changer.

 

[Lbgem]

All RNA viruses must produce at least a transient dsRNA intermediate. In replicating + or - RNA, you have to produce the opposite sense RNA, thus forming a dsRNA molecule. Also remember that there doesn't have to be an entire dsRNA genome. Any partially annealed dsRNA is enough for a dsRNA binding protein to bind. Many endogenous human anti-viral defenses already act to target dsRNA e.g. PKR induced inhibition of translation.

This theoretical broad-spectrum anti-viral links the endogenous dsRNA binding proteins to apoptosis inducing machinery. Cool mechanism, but color me unexcited until we see some human trials. Wayyy too many in vitro and mouse studies don't pan out then turn into usable drugs. More often then not, the new drug is also an incremental improvement, not a complete game changer.

I would agree with the last part of your statement in mouse/in vitro studies sometimes not translating into humans.

But I do think it is something to be excited about and it is a very different mechanism. I would argue that if it works in humans it would be a game changer because of the difficulty in developing resistance mechanisms to it. It's not like the virus can NOT produce dsRNA. I was curious why it wasn't published in Science or Nature however as it seems to be pretty interesting. Perhaps they were waiting for human experiments like you are .

And I wasn't discounting dsRNA being formed in the herpes case. I would just be surprised if DRACO worked for that virus because it does have a latent cycle in which no dsRNA is produced/and during which time it evades the immune system. I would think it would work for the lytic cycle, just not the latent one, so no way to permanently cure it using this mechanism.

 

[DoctwoB]

I would agree with the last part of your statement in mouse/in vitro studies sometimes not translating into humans.

But I do think it is something to be excited about and it is a very different mechanism. I would argue that if it works in humans it would be a game changer because of the difficulty in developing resistance mechanisms to it. It's not like the virus can NOT produce dsRNA. I was curious why it wasn't published in Science or Nature however as it seems to be pretty interesting. Perhaps they were waiting for human experiments like you are .

Any new mechanism based drugs are a good thing, but there's plenty of possible resistance mechanisms. Altered RNA sequences to reduce affinity for binding proteins. Viral induced up-regulation of anti-apoptotic machinery. Alteration of viral protease structure to cleave the peptide.

intra-cellular delivery of a large protein drug is also a major concern.

Once again, there is some cause for optimism, but I wouldn't get our hopes up just yet.

 

[Lbgem]

Any new mechanism based drugs are a good thing, but there's plenty of possible resistance mechanisms. Altered RNA sequences to reduce affinity for binding proteins. Viral induced up-regulation of anti-apoptotic machinery. Alteration of viral protease structure to cleave the peptide.

intra-cellular delivery of a large protein drug is also a major concern.

Once again, there is some cause for optimism, but I wouldn't get our hopes up just yet.

Hm, I would argue it's much harder to alter larger stretches/portions of RNA sequences than changing one or two nucleotides (usually the cause of drug resistance). Yes, I am assuming here that these dsRNA binding proteins recognize more than just one or two specific regions, as they work against a broad number of viruses, which don't share the same RNA. I don't follow the alteration of viral protease structure though - it's meant to cleave viral proteins, not the host binding proteins.

But agree with you on your last point; I share your concern about the delivery mechanism. I would say that's usually where drugs fail in translating from mice to humans.

 

[Canaan]

All RNA viruses must produce at least a transient dsRNA intermediate. In replicating + or - RNA, you have to produce the opposite sense RNA, thus forming a dsRNA molecule. Also remember that there doesn't have to be an entire dsRNA genome. Any partially annealed dsRNA is enough for a dsRNA binding protein to bind. Many endogenous human anti-viral defenses already act to target dsRNA e.g. PKR induced inhibition of translation.

This theoretical broad-spectrum anti-viral links the endogenous dsRNA binding proteins to apoptosis inducing machinery. Cool mechanism, but color me unexcited until we see some human trials. Wayyy too many in vitro and mouse studies don't pan out then turn into usable drugs. More often then not, the new drug is also an incremental improvement, not a complete game changer.

I'm not an expert in this field, but if the drug induces apoptosis I assume it means that it will prove useless against the most deadly virus known to man (Rabies) considering it infects the brain?

Also, something interesting I found is that there is another drug that induces apoptosis for infected cells (like DRACO) and increases interferon production, but the FDA rejected the drug (Ampligen) in 2009 (only approved in Belgium). One can only hope this new drug doesn't suffer the same fate as Ampligen.