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Author Topic: Could we possibily have another "Holy Grail" in the making?  (Read 2905 times)

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Offline veritas

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Could we possibily have another "Holy Grail" in the making?
« on: February 02, 2010, 06:05:43 AM »

Another broad-spectrum anti-viral:

" "We provide evidence that the small molecule binds to both cellular and viral membranes, but its preferential ability to inactivate viral membranes comes from its ability to exploit the biogenic reparative ability of metabolically active cells versus static viral membranes," he said. "That is, at antiviral concentrations, any damage it does to the cell's membrane can be repaired, while damage done to static viral membranes, which have no inherent regenerative capacity, is permanent and irreversible."

It's called Lj001.

http://www.scienceblog.com/cms/researchers-find-broad-spectrum-antiviral-fights-multitude-viruses.html?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+scienceblogrssfeed+%28Science+Blog%29

Here the science background:

http://www.pnas.org/content/suppl/2010/01/28/0909587107.DCSupplemental/pnas.200909587SI.pdf

Here the abstract:


http://www.pnas.org/content/early/2010/01/27/0909587107.

I like the focus of these broad-spectrum anti-virals.

We just might catch a break one of these days.

It's  Happening !

v



Offline Inchlingblue

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Re: Could we possibily have another "Holy Grail" in the making?
« Reply #1 on: February 02, 2010, 10:51:19 AM »
This is an exciting discovery.

There are a few things I don't understand about these broad-spectrum antivirals (and this one in particular):

1) Assuming it is not toxic to other cells (and this one appears not to be at antiviral concentrations), how would this be used in treatment for someone who has HIV? Say a person is undetectable. I guess it would depend on how long the antiviral remains in the body?

2) No mention about whether this is something that a virus, HIV in particular, would be able to evade through resistance. Although it seems it would not, as long as all viruses are attacked by the antiviral before they're able to invade cells. The only way resistance can happen is if the virus can make more copies of itself which it can only do after invading a cell. It's also possible that any mutation to the viral envelope might render the virus inactive anyway.

All in all, a very promising discovery.
« Last Edit: February 02, 2010, 10:56:17 AM by Inchlingblue »

Offline J220

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Re: Could we possibily have another "Holy Grail" in the making?
« Reply #2 on: February 02, 2010, 11:06:01 AM »
Wow another great discovery, although I too have questions about the application of this antiviral.

At this early stage, and with the limited information provided (coupled with my own limited knowledge of biochemistry) it would seem that this would make a fantastic preventive treatment for high risk groups, although not a vaccine.

And since this is a compound I don't think you can "train" the immune system to create it so it's perpetually present in your system. And Although I guess it could be used as an ongoing treatment for those infected, the fact that it does damage healthy cells, albeit it temporarily, I don't think it will be a good thing to take on a daily basis.

But the big question I have is this: what does Lj001 do to infected cells? Could it be possible that, following along the lines of the method of action of Bavituximab, it could also fatally disrupt the cell membranes of infected cells? Would the exposed PS on infected cells cause Lj001 to destroy them? I wonder.


I hope they test this substance on infected cell cultures to see the effect. Because I tell you, if this is able to kill infected cells, in addition to free floating virus, guess what everybody, time to celebrate, because we may have a winner...
« Last Edit: February 02, 2010, 11:09:34 AM by J220 »
"Hope is my philosophy
Just needs days in which to be
Love of Life means hope for me
Born on a New Day" - John David

Offline veritas

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Re: Could we possibily have another "Holy Grail" in the making?
« Reply #3 on: February 02, 2010, 11:20:23 AM »

Guys,

All good questions, but too early to tell.

Inch,

I agree with you that the virus probably wouldn't be able to mutate against Lj001 since the antibody doesn't go after the virus itself, so the virus doesn't know it's being attacked.

J220,

You asked the million dollar question: "What does Lj001 do to the infected cells in reservoirs, if anything?
Time will tell.

Stay tuned,

v



Offline Inchlingblue

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Re: Could we possibily have another "Holy Grail" in the making?
« Reply #4 on: February 02, 2010, 11:30:55 AM »
Guys,

All good questions, but too early to tell.

Inch,

I agree with you that the virus probably wouldn't be able to mutate against Lj001 since the antibody doesn't go after the virus itself, so the virus doesn't know it's being attacked.


The reasons I'm theorizing that the virus won't be able to evade LJ001 are not because it does not go after the virus itself. I'm under the impression it does go after the virus itself, specifically the viral envelope.

At any rate, I agree it's too soon to tell about many of the specifics.

"Once we started testing more and more, we realized that it was only targeting enveloped viruses," said Alexander Freiberg, director of UTMB's Robert E. Shope, M.D. Laboratory, the Biosafety Level 4 lab where much of the cell-culture work was done, as well as mouse studies with Ebola and Rift Valley fever viruses. "We followed up and determined that it was somehow changing the lipid envelope to prevent the fusion of the virus particle with the host cell."

LINK:

http://www.sciencedaily.com/releases/2010/02/100201113801.htm

Offline veritas

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Re: Could we possibily have another "Holy Grail" in the making?
« Reply #5 on: February 02, 2010, 11:42:09 AM »

Inch.

This quote gave me the impression that it will go after the cell membrane that the virus is trying to enter
without doing permanent damage to the host cell:

"That is, at antiviral concentrations, any damage it does to the cell's membrane can be repaired, while damage done to static viral membranes, which have no inherent regenerative capacity, is permanent and irreversible"

I could be wrong.

v

Offline Inchlingblue

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Re: Could we possibily have another "Holy Grail" in the making?
« Reply #6 on: February 02, 2010, 12:01:00 PM »
Inch.

This quote gave me the impression that it will go after the cell membrane that the virus is trying to enter
without doing permanent damage to the host cell:

"That is, at antiviral concentrations, any damage it does to the cell's membrane can be repaired, while damage done to static viral membranes, which have no inherent regenerative capacity, is permanent and irreversible"

I could be wrong.

v

Yes, but it's also attacking the virus itself, hence the question of possible resistance. LJ001 affects both the cell membrane as well as the viral membrane but the cell can regenerate and correct the damage to its membrane whereas the virus is not able to do that, making the damage to the virus membrane permanent and irreversible.

"We provide evidence that the small molecule binds to both cellular and viral membranes, but its preferential ability to inactivate viral membranes comes from its ability to exploit the biogenic reparative ability of metabolically active cells versus static viral membranes," he said. "That is, at antiviral concentrations, any damage it does to the cell's membrane can be repaired, while damage done to static viral membranes, which have no inherent regenerative capacity, is permanent and irreversible."

LINK:

http://www.rdmag.com/News/Feeds/2010/02/life-sciences-researchers-find-broad-spectrum-antiviral-that-fig/


As far as resistance, it's possible that damage to the viral membrane (envelope) can render the virus ineffective since it seems to be one of it's more structured regions. Maybe that's what that researcher is implying when he uses the words "permanent and irreversible." Too soon to tell I guess.
« Last Edit: February 02, 2010, 04:12:23 PM by Inchlingblue »

Offline veritas

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Re: Could we possibily have another "Holy Grail" in the making?
« Reply #7 on: February 03, 2010, 05:41:27 AM »

Inch,

This one really is too early to tell. We don't know what the half-life is or if the therapy is strong enough to mount a sustained response.
However....
This study lends further evidence to the fact that lipids are a "good" target on the virus and this bodes
well for anti-ps antibodies (Bavituximab) which is much further along in development.

v

Offline J220

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Re: Could we possibily have another "Holy Grail" in the making?
« Reply #8 on: February 04, 2010, 02:15:57 AM »
Hey guys,

So I corresponded with Dr. Benhur Lee, lead UCLA researcher of this project, and asked him some questions about Lj001. He was generous enough to reply, and he gave me some more expanded information on this. He also gave me permission to share with everyone here what he replied to me. His only request (as seen in his reply) is that no part of his response is taken out of context. That's why rather than paraphrase his reply I'll just copy it to keep it accurate. The parts in italics were the questions I posed to him in my original email:
--------------------------------

Dear J.

Thank you for your interest. I am pleasantly surprised to see how much attention/discussion it has engendered in forums.poz.com. Clearly, there are informed readers that have asked very germane questions.

Let me try and answer your questions the best I can . . . but I apologize for being a bit nebulous because we have since found out the exact mechanism (which is entirely novel and unexpected) but the patent on this mechanistic discovery has not been filed so I have been advised not to talk specifically about it in public.

(1) what effect can this compound have on HIV-infected cells? What is your hypothesis regarding any benefit to those already infected with the virus, as opposed to the prevention of initial infection?

The compound binds specifically [to] lipid membranes, both cellular and viral membranes. All I can say now is the compound needs to be "activated" in order to effectuate its damaging effects on membrane components (such as phospholipids and cholesterol). The damage is not specific to viral membranes per se (like HIV's) but the reason why it is antiviral at the concentration used is that any damage it does to metabolically active cellular membranes can be repaired by the cell's biogenic repair machinery whereas viral membranes are static and cannot recover from the damage.

That being said, since we know now how to activate the compound (I wish I can be more specific, but I hope you understand the restrictions I am under) we are currently working on strategies to specifically target the activation of the compound on viruses or on virally infected cells. Your question of whether we can specifically target and destroy virally infected cells is something we are exploring by targeted activation of the compound.

   
(2) Do you know if LJ001 also interacts with aminophospholipid, and could cause the destruction of the infected cell?

No, it does not target a specific aminophospholipid or externalized PS on infected cells as suggested by some of the other bloggers. It does target other features of specific phospholipids and most likely, membrane cholesterol as well. Injection of the compound into mice once a day for 7 days resulted in no toxicity monitored by complete chemistry panels and CBC EXCEPT for a slight elevantion in trigylcerides and cholesterol (also consistent with its lipid targeting mechanism).

In summary, we are working hard on getting out the next paper on our second generation compounds where we could better explain its molecular mechanism of action. Unfortunately, science does not progress as fast as we want to . . . it took us 4 years just to get to this point from our initial discovery of the compound--it is difficult to convince scientists when you propose a paradigm shift of how an antiviral should work.

You may feel free to post some or all of my comments on the forum, please just don't take any of my comments out of context.

Best regards,

Benhur

------------------------------------------------------
"Hope is my philosophy
Just needs days in which to be
Love of Life means hope for me
Born on a New Day" - John David

Offline veritas

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Re: Could we possibily have another "Holy Grail" in the making?
« Reply #9 on: February 04, 2010, 06:13:21 AM »

J220,

It's posts like yours that renew faith in the diligent work being done to fight this disease.
 
 A "BRAVO! "goes out to Dr. Lee for taking the time to answer your questions  and allowing his comments to be posted for all those who are struggling with HIV. (The hope goes on!).He certainly has clarified some of the questions I had.

What amazes me in Dr. Lee's comments is that he has found another new paradigm to potentially defeat HIV.. This discovery is certainly not a "me-too" find. I look forward to additional information on this exciting research , as it progresses through the stages of development.

Dr. Lee's comments concerning the difficulty in convincing scientists when a new paradigm is proposed, is certainly true.  I believe that many scientists assimilate the new data based on incompatable older theory. If you would like to learn more , concerning this issue, read: "The Structure of Scientific Revolutions" by Thomas S. Kuhn. 

A "BRAVO" to YOU J, for  sharing your information for the benefit of all.

It's Happening!

v

Offline Inchlingblue

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Re: Could we possibily have another "Holy Grail" in the making?
« Reply #10 on: February 04, 2010, 10:17:37 AM »
J220:

Thank you for that. Dr. Lee is very gracious. Very nice of him to have taken the time to respond and to do so very clearly. The original articles mentioned that they were close to finding out what is the exact mechanism of viral membrane inactivation and it seems from his response that they have found what it is, which is very important.

Below are some other articles that have appeared since the original ones, including one from MedPage Today that has some new information. It states: Analysis of the compound's behavior in serum showed that it did not reach a useful level for two hours after injection and that its half-life in the body was only about four hours. While this might not seem ideal, it's too soon to know; it's short half-life can be a good thing as far as avoiding toxicity.

http://www.medpagetoday.com/InfectiousDisease/GeneralInfectiousDisease/18273

http://www.aidsmeds.com/articles/hiv_antiviral_new_1667_17957.shtml

http://www.scientistlive.com/European-Science-News/Pharmacology/Antiviral_that_fights_multitude_of_viruses/24034/

http://www.popsci.com/science/article/2010-02/lj001-acts-antibiotics-viruses
« Last Edit: February 04, 2010, 01:00:17 PM by Inchlingblue »

Offline veritas

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Re: Could we possibily have another "Holy Grail" in the making?
« Reply #11 on: February 05, 2010, 09:31:20 AM »

Inch,

From your posted article:


" It states: Analysis of the compound's behavior in serum showed that it did not reach a useful level for two hours after injection and that its half-life in the body was only about four hours. While this might not seem ideal, it's too soon to know; it's short half-life can be a good thing as far as avoiding toxicity"

True, it might avoid toxicity, however, it also means they must work out the kinks for steady state plasma concentrations. Perhaps that is what Dr. Lee was referring to with respect to "activating the compound". I hope he does it !

Thanks for finding that Inch,

v

 


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