1: Ann N Y Acad Sci. 2005 Nov;1056:279-92.

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Novel Drugs and Vaccines Based on the Structure and Function of HIV Pathogenic Proteins Including Nef.

Azad AA.

Faculty of Health Sciences, Medical School, University of Cape Town, Anzio Road, Observatory, 7925, Cape Town, South Africa. a_azad05@yahoo.com.au.

Evidence is presented to suggest that HIV-1 accessory protein Nef could be involved in AIDS pathogenesis. When present in extracellular medium, Nef causes the death of a wide variety of cells in vitro and may therefore be responsible for the depletion of bystander cells in lymphoid tissues during HIV infection. When present inside the cell, Nef could prevent the death of infected cells and thereby contribute to increased viral load. Intracellular Nef does this by preventing apoptosis of infected cells by either inhibiting proteins involved in apoptosis or preventing the infected cells from being recognized by CTLs. Neutralization of extracellular Nef could prevent the death of uninfected immune cells and thereby the destruction of the immune system. Neutralization of intracellular Nef could hasten the death of infected cells and help reduce the viral load. Nef is therefore a very important molecular target for developing therapeutics that slow progression to AIDS. The N-terminal region of Nef and the naturally occurring bee venom mellitin have very similar primary and tertiary structures, and they both act by destroying membranes. Chemical analogs of a mellitin inhibitor prevent Nef-mediated cell death and inhibit the interaction of Nef with cellular proteins involved in apoptosis. Naturally occurring bee propolis also contains substances that prevent Nef-mediated cell lysis and increases proliferation of CD4 cells in HIV-infected cultures. These chemical compounds and natural products are water soluble and nontoxic and are therefore potentially very useful candidate drugs.

PMID: 16387695 [PubMed - in process]

2: Mol Pharmacol. 2001 Aug;60(2):341-7.

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A peptide derived from bee venom-secreted phospholipase A2 inhibits replication of T-cell tropic HIV-1 strains via interaction with the CXCR4 chemokine receptor.

Fenard D, Lambeau G, Maurin T, Lefebvre JC, Doglio A.

Laboratoire de Virologie, Institut National de la Sante et de la Recherche Medicale U526, Faculte de Medecine, Nice, France.

We have previously shown that secreted phospholipases A2 (sPLA2) from bee and snake venoms have potent anti-human immunodeficiency virus (HIV) activity. These sPLA2s block HIV-1 entry into host cells through a mechanism linked to sPLA2 binding to cells. In this study, 12 synthetic peptides derived from bee venom sPLA2 (bvPLA2) have been tested for inhibition of HIV-1 infection. The p3bv peptide (amino acids 21 to 35 of bvPLA2) was found to inhibit the replication of T-lymphotropic (T-tropic) HIV-1 isolates (ID(50) = 2 microM) but was without effect on monocytotropic (M-tropic) HIV-1 isolates. p3bv was also found capable of preventing the cell-cell fusion process mediated by T-tropic HIV-1 envelope. Finally, p3bv can inhibit the binding of radiolabeled stromal cell-derived factor (SDF)-1alpha, the natural ligand of CXCR4, and the binding of 12G5, an anti-CXCR4 monoclonal antibody. Taken together, these results indicate that p3bv blocks the replication of T-tropic HIV-1 strains by interacting with CXCR4. Its mechanism of action however appears distinct from that of bvPLA2 because the latter inhibits replication of both T-tropic and M-tropic isolates and does not compete with SDF-1alpha and 12G5 binding to CXCR4.

PMID: 11455021 [PubMed - indexed for MEDLINE]

3: Posit Aware. 1997 Mar-Apr;8(2):28-35.

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Whole body health.

Austin E.

AIDS: Alternative therapies, widely used by Americans, include yoga, relaxation techniques, and herbal medications, as well as less conventional and more experimental treatments. The AIDS Research Center in Seattle is conducting the largest study of alternative therapies. Many alternative therapies are used as complements to traditional treatments, and can make a disease easier to manage. Several categories of alternative medicines are detailed: acupuncture and other Chinese treatments, natural treatments including herbal medicine and aromatherapy, and mind-body treatments such as hypnosis and biofeedback. Patients are cautioned to avoid five dangerous therapies: chelation therapy, colonic irrigation, bee venom therapy, hydrogen peroxide injections, and unlabeled medicines. Contact telephone numbers for alternative therapies are listed.

Publication Types:

·       Newspaper Article

PMID: 11364455 [PubMed - indexed for MEDLINE]

4: Med Res Rev. 2000 Sep;20(5):323-49.

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Current lead natural products for the chemotherapy of human immunodeficiency virus (HIV) infection.

De Clercq E.

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. erik.declerq@rega.kuleven.ac.be

A large variety of natural products have been described as anti-HIV agents, and for a portion thereof the target of interaction has been identified. Cyanovirin-N, a 11-kDa protein from Cyanobacterium (blue-green alga) irreversibly inactivates HIV and also aborts cell-to-cell fusion and transmission of HIV, due to its high-affinity interaction with gp120. Various sulfated polysaccharides extracted from seaweeds (i.e., Nothogenia fastigiata, Aghardhiella tenera) inhibit the virus adsorption process. Ingenol derivatives may inhibit virus adsorption at least in part through down-regulation of CD4 molecules on the host cells. Inhibition of virus adsorption by flavanoids such as (-)epicatechin and its 3-O-gallate has been attributed to an irreversible interaction with gp120 (although these compounds are also known as reverse transcriptase inhibitors). For the triterpene glycyrrhizin (extracted from the licorice root Glycyrrhiza radix) the mode of anti-HIV action may at least in part be attributed to interference with virus-cell binding. The mannose-specific plant lectins from Galanthus, Hippeastrum, Narcissus, Epipac tis helleborine, and Listera ovata, and the N-acetylgl ucosamine-specific lectin from Urtica dioica would primarily be targeted at the virus-cell fusion process. Various other natural products seem to qualify as HIV-cell fusion inhibitors: the siamycins [siamycin I (BMY-29304), siamycin II (RP 71955, BMY 29303), and NP-06 (FR901724)] which are tricyclic 21-amino-acid peptides isolated from Streptomyces spp that differ from one another only at position 4 or 17 (valine or isoleucine in each case); the betulinic acid derivative RPR 103611, and the peptides tachyplesin and polyphemusin which are highly abundant in hemocyte debris of the horseshoe crabs Tachypleus tridentatus and Limulus polyphemus, i.e., the 18-amino-acid peptide T22 from which T134 has been derived. Both T22 and T134 have been shown to block T-tropic X4 HIV-1 strains through a specific antagonism with the HIV corecept or CXCR4. A number of natural products have been reported to interact with the reverse transcriptase, i.e., baicalin, avarol, avarone, psychotrine, phloroglucinol derivatives, and, in particular, calanolides (from the tropical rainforest tree, Calophyllum lanigerum) and inophyllums (from the Malaysian tree, Calophyllum inophyllum). The natural marine substance illimaquinone would be targeted at the RNase H function of the reverse transcriptase. Curcumin (diferuloylmethane, from turmeric, the roots/rhizomes of Curcuma spp), dicaffeoylquinic and dicaffeoylt artaric acids, L-chicoric acid, and a number of fungal metabolites (equisetin, phomasetin, oteromycin, and integric acid) have all been proposed as HIV-1 integrase inhibitors. Yet, we have recently shown that L-c hicoric acid owes its anti-HIV activity to a specific interaction with the viral envelope gp120 rather than integrase. A number of compounds would be able to inhibit HIV-1 gene expression at the transcription level: the flavonoid chrysin (through inhibition of casein kinase II, the antibacter ial peptides melittin (from bee venom) and cecropin, and EM2487, a novel substance produced by Streptomyces.

Publication Types:

·       Review

PMID: 10934347 [PubMed - indexed for MEDLINE]

5: AIDS Res Hum Retroviruses. 1997 Nov 20;13(17):1525-32.

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A synthetic peptide corresponding to the carboxy terminus of human immunodeficiency virus type 1 transmembrane glycoprotein induces alterations in the ionic permeability of Xenopus laevis oocytes.

Comardelle AM, Norris CH, Plymale DR, Gatti PJ, Choi B, Fermin CD, Haislip AM, Tencza SB, Mietzner TA, Montelaro RC, Garry RF.

Graduate Program in Molecular and Cellular Biology, Tulane University, New Orleans, Louisiana 70112, USA.

The carboxy-terminal 29 amino acids of the human immunodeficiency virus type 1 transmembrane glycoprotein (HIV-1 TM) are referred to as lentivirus lytic peptide 1 (LLP-1). Synthetic peptides corresponding to LLP-1 have been shown to induce cytolysis and to alter the permeability of cultured cells to various small molecules. To address the mechanisms by which LLP-1 induces cytolysis and membrane permeability changes, various concentrations of LLP-1 were incubated with Xenopus laevis oocytes, and two-electrode, voltage-clamp recording measurements were performed. LLP-1 at concentrations of 75 nM and above induced dramatic alterations in the resting membrane potential and ionic permeability of Xenopus oocytes. These concentrations of LLP-1 appeared to induce a major disruption of plasma membrane electrophysiological integrity. In contrast, concentrations of LLP-1 of 20-50 nM induced changes in membrane ionic permeability that mimic changes induced by compounds, such as the bee venom peptide melittin, that are known to form channel-like structures in biological membranes at sublytic concentrations. An analog of LLP-1 with greatly reduced cytolytic activity failed to alter the electrophysiological properties of Xenopus oocytes. Thus, by altering plasma membrane ionic permeability, the carboxy terminus of TM may contribute to cytolysis of HIV-1-infected CD4+ cells.

Publication Types:

·       Review

PMID: 9390752 [PubMed - indexed for MEDLINE]

6: Protein Sci. 1992 Nov;1(11):1454-64.

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A molecular model for membrane fusion based on solution studies of an amphiphilic peptide from HIV gp41.

Fujii G, Horvath S, Woodward S, Eiserling F, Eisenberg D.

Molecular Biology Institute, University of California, Los Angeles 90024-1570.

The mechanism of protein-mediated membrane fusion and lysis has been investigated by solution-state studies of the effects of peptides on liposomes. A peptide (SI) corresponding to a highly amphiphilic C-terminal segment from the envelope protein (gp41) of the human immunodeficiency virus (HIV) was synthesized and tested for its ability to cause lipid membranes to fuse together (fusion) or to break open (lysis). These effects were compared to those produced by the lytic and fusogenic peptide from bee venom, melittin. Other properties studied included the changes in visible absorbance and mean particle size, and the secondary structure of peptides as judged by CD spectroscopy. Taken together, the observations suggest that protein-mediated membrane fusion is dependent not only on hydrophobic and electrostatic forces but also on the spatial arrangement of the amino acid residues to form an amphiphilic structure that promotes the mixing of the lipids between membranes. A speculative molecular model is proposed for membrane fusion by alpha-helical peptides, and its relationship to the forces involved in protein-membrane interactions is discussed.

PMID: 1303764 [PubMed - indexed for MEDLINE]