New compound shows promise in halting HIV spread

[Optimistic]

Just want to share this article with everyone...

http://www.eurekalert.org/pub_releases/2007-01/tu-ncs013107.php

Justin

[Ihavehope]

Sounds promising. I am pretty sad that the Valporic Acid theory of curing AIDS didn't work out. I knew it sounded to good to be true but that just shows us how vicious this virus can be.

[Jake72]

"Developed by Temple University researchers, 2-5AN6B could someday work as an effective treatment for HIV especially in conjunction with current drug treatments."

Oh goody, even MORE expensive pills and side effects to deal with...

Sorry, folks, as much as I'm glad to see the possibility of a larger arsenal of anti-HIV weapons, I'd really like to see us receiving fewer medications (i.e. therapeutic vaccination, effective STIs), not more.

[bimazek]

2-5AN6B is a nuclease-resistant 2-5A agonist analog

2-5AN6B is an enzyme capable of cleaving the phosphodiester bonds between the nucleotide subunits of nucleic acids

A nuclease is an enzyme capable of cleaving the phosphodiester bonds between the nucleotide subunits of nucleic acids. Older papers may use terms such as "polynucleotidase" or "nucleodepolymerase"

An agonist is a molecule that selectively binds to a specific receptor and triggers a response in the cell. It mimics the action of an endogenous biochemical molecule (such as hormone or neurotransmitter) that binds to the same receptor. It is a drug molecule (synthesized outside an organism) that reproduces the action of an endogenous natural biochemical (synthesized inside an organism). An agonist is the opposite of an antagonist in the sense that while an antagonist also binds to the receptor, the antagonist does not activate the receptor and actually blocks it from activation by agonists. A partial agonist (such as buspirone, aripiprazole, bifeprunox or norclozapine) activates a receptor, but only produces a partial physiological response compared to a full agonist. A co-agonist works with other co-agonists to produce the desired effect together. Receptors can be activated or inactivated by endogenous (such as hormones and neurotransmitters) or exogenous (such as drugs) agonists and antagonists, resulting in stimulating or inhibiting the cell. To see how an agonist may activate a receptor see this link. Recently a novel theory called Functional Selectivity has been proposed that broadens the conventional definition of pharmacology.

In the late 1960's, scientists Stewart Linn and Werner Arber isolated examples of the two types of enzymes responsible for phage growth restriction in Escherichia coli (E. coli) bacteria. One of these enzymes cleaved methylated DNA, while the other cleaved unmethylated DNA at a wide variety of locations along the length of the molecule. The first type of enzyme was called a "methylase" while the other was called a "restriction nuclease." These enzymatic tools were important to scientists who were gathering the tools needed to "cut and paste" DNA molecules. What was needed now was a tool that would cut DNA at specific sites, rather than at random sites along the length of the molecule, so that scientists could cut DNA molecules in a predictable and reproducible way.

[edit] Site-specific nuclease

This important development came when H.O. Smith, K.W. Wilcox, and T.J. Kelley, working at Johns Hopkins University in 1968, isolated and characterized the first restriction nuclease whose functioning depended on a specific DNA nucleotide sequence. Working with Haemophilus influenzae bacteria, this group isolated an enzyme, called HindII, that always cut DNA molecules at a particular point within a specific sequence of six base pairs. This sequence is:

5' G T ( pyrimidine: T or C) ( purine: A or G) A C 3'
3' C A ( purine: A or G) ( pyrimidine: T or C) T G 5'

They found that the HindII enzyme always cuts directly in the center of this sequence. Wherever this particular sequence of six base pairs occurs unmodified in a DNA molecule, HindII will cleave both DNA backbones between the 3rd and 4th base pairs of the sequence. Moreover, HindII will only cleave a DNA molecule at this particular site. For this reason, this specific base sequence is known as the "recognition sequence" for HindII.

Endonucleases and DNA fragments

A restriction endonuclease functions by "scanning" the length of a DNA molecule. Once it encounters its particular specific recognition sequence, it will bond to the DNA molecule and makes one cut in each of the two sugar-phosphate backbones of the double helix. The positions of these two cuts, both in relation to each other, and to the recognition sequence itself, are determined by the identity of the restriction endonuclease used to cleave the molecule in the first place. Different endonucleases yield different sets of cuts, but one endonuclease will always cut a particular base sequence the same way, no matter what DNA molecule it is acting on. Once the cuts have been made, the DNA molecule will break into fragments.

[edit] Endonucleases and sticky ends

Not all restriction endonucleases cut symmetrically and leave blunt ends like HindII described above. Many endonucleases cleave the DNA backbones in positions that are not directly opposite each other. For example, the nuclease EcoRI has the following recognition sequence



Inhibition of Morphine-potentiated HIV-1 Replication in Peripheral Blood Mononuclear Cells with the Nuclease-resistant 2-5A Agonist Analog, 2-5A(N6B)

The compound, 2-5AN6B is a nuclease-resistant 2-5A agonist analog. In these studies using morphine-treated peripheral blood mononuclear cell cultures researchers found that 2-5AN6B, but not AZT or saquinavir completely reversed morphine-induced potentiation of HIV-1 infection. Treatment of peripheral blood mononuclear cell cultures with 2-5AN6B increased RNase L activity in control peripheral blood mononuclear cell cultures, in morphine-treated peripheral blood mononuclear cell cultures and in morphine-treated, HIV-1-infected peripheral blood mononuclear cells. The researchers also found that 2-5AN6B enhanced expression of both IFN-" and IFN-(. The increased expression of IFN-( was associated with a significant increase in expression of RANTES and monocyte chemotactic protein-1, chemokines that may inhibit HIV-1 infection by blocking viral attachment to CCR2 and CCR5 co-receptors. By adding 2-5AN6B to the cultured morphine-treated peripheral blood mononuclear cells, the researchers were able to reverse the morphine-potentiated HIV-1 infection of the cells. Homan, J.W., Steele, A.D., Martinand-Mari, C., Rogers, T.J., Henderson, E.E., Charubala, R., Pfleiderer, W., Reichenbach, N.L., and Suhadolnik, R.J. J Acquir Immune Defic Syndr.,30(1), pp. 9-20, May 1, 2002.




















A gonadotropin-releasing hormone analogue, also known as a GnRH analogue, (sometimes analog) is a synthetic peptide drug modeled after the human hypothalamic gonadotropin-releasing hormone (GnRH). A GnRH analogue is designed to interact with the GnRH receptor and modify the release of pituitary gonadotropins FSH and LH for therapeutic purposes. Shortly after the discovery of GnRH by Nobel laureates Guillemin and Schally researchers tried to modify the GnRH decapeptide with the intent to synthesize stimulating and blocking variants.

Two types of analogues have to be distinguished:

Agonists

    Main article: gonadotropin-releasing hormone agonist

A gonadotropin-releasing hormone agonist (GnRH agonist) is an analogue that activates the GnRH receptor resulting in increased secretion of FSH and LH. Initially it was thought that agonists would be able to be used as potent and prolonged stimulators of pituitary gonadotropin release, but it was soon recognized that agonists, after their initial stimulating action – termed a “flare” effect -, eventually caused a paradoxical and sustained drop in gonadotropin secretion. This second effect was termed “downregulation” and can be observed after about 10 days. While this phase is reversible it can be maintained with further GnRH agonist use for a long time.

[Central79]

Sounds promising. I am pretty sad that the Valporic Acid theory of curing AIDS didn't work out. I knew it sounded to good to be true but that just shows us how vicious this virus can be.

I haven't given up on valproic acid yet. All that's happened is there's been one study that didn't have the same results as the original study. I've glanced at the second study, and didn't think it was all that. I know David Margolis who published the original research has gone back to have another go and recruitment for his trial ends 2008, so I'm hoping something good will be published then...

Even if valproic acid can't eradicate HIV in the body, I think significant reduction of viral reservoirs is a useful thing to achieve - it might mean lower doses of another modality like radioimmunotherapy being able to clear the infection at a lower dose. They did a study in mice recently and the radioimmunotherapy cleared 99% of HIV in the spleens of infected mice. I can't find anything about whether they're going on to try it in humans now, but I think that's another cool avenue.

Matt x.