Three-Dimensional Structure-Activity Analysis of a Series of Porphyrin Derivatives with Anti-HIV-1 Activity Targeted to the V3 Loop of the gp120 Envelope Glycoprotein of the Human Immunodeficiency Virus Type 1

Debnath, Asim K.; Jiang, Shibo; Strick, N.; Lin, Kang; Haberfield, Paul; Neurath, A. R.

doi:10.1021/jm00034a007

Cited by 85 publications

(52 citation statements)

References 25 publications

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“…Since the primary interaction appears to be dependent on charge density rather than a particular structural motif (57), it seems unlikely that the specificity essential for effective therapeutic treatment is present. This does not bode well for drug development based on polyanions such as sulfated polysaccharides (2,24,35), carboxylated albumins (26,51), porphyrins (13,49), or DNA or RNA derivatives (31). Nevertheless, the unusual basicity observed for the CXCR4-using viruses may, in this particular case, permit anion-based intervention.…”

Section: Discussionmentioning

confidence: 99%

Oligomeric Modeling and Electrostatic Analysis of the gp120 Envelope Glycoprotein of Human Immunodeficiency Virus

Kwong

Wyatt

Sattentau

et al. 2000

J Virol

247

196

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The human immunodeficiency virus envelope glycoproteins, gp120 and gp41, function in cell entry by binding to CD4 and a chemokine receptor on the cell surface and orchestrating the direct fusion of the viral and target cell membranes. On the virion surface, three gp120 molecules associate noncovalently with the ectodomain of the gp41 trimer to form the envelope oligomer. Although an atomic-level structure of a monomeric gp120 core has been determined, the structure of the oligomer is unknown. Here, the orientation of gp120 in the oligomer is modeled by using quantifiable criteria of carbohydrate exposure, occlusion of conserved residues, and steric considerations with regard to the binding of the neutralizing antibody 17b. Applying similar modeling techniques to influenza virus hemagglutinin suggests a rotational accuracy for the oriented gp120 of better than 10°. The model shows that CD4 binds obliquely, such that multiple CD4 molecules bound to the same oligomer have their membrane-spanning portions separated by at least 190 Å. The chemokine receptor, in contrast, binds to a sterically restricted surface close to the trimer axis. Electrostatic analyses reveal a basic region which faces away from the virus, toward the target cell membrane, and is conserved on core gp120. The electrostatic potentials of this region are strongly influenced by the overall charge, but not the precise structure, of the third variable (V3) loop. This dependence on charge and not structure may make electrostatic interactions between this basic region and the cell difficult to target therapeutically and may also provide a means of viral escape from immune system surveillance.The human immunodeficiency viruses (types 1 [HIV-1] and 2 [HIV-2]) and related simian viruses (SIVs) cause the depletion and functional dysregulation of CD4 ϩ lymphocytes, resulting in the development of AIDS. The HIV envelope contains two glycoproteins: gp120, the exterior receptor-binding component, and its noncovalently interacting partner, gp41, the transmembrane envelope glycoprotein. Only half of gp41 is exposed in the ectodomain; the other half, separated by a transmembrane region, is thought to anchor the envelope complex to the underlying matrix. New infections are initiated by interaction of gp120 with the N-terminal membrane-distal domain of CD4, a glycoprotein on the surface of specific cells of the immune system (12, 29). A second interaction of gp120, with a member of the chemokine receptor family, primarily CCR5 or CXCR4, is believed to trigger conformational changes in gp41, which ultimately mediates virus-cell membrane fusion (20,38).HIV receptor binding takes place in the context of an oligomeric viral spike. Atomic-level structures have been determined for many of the component molecules: the entire extracellular portion of CD4 (60), the complex of monomeric core gp120 (a truncated version of gp120 with deletions of the gp41-interactive region at the N and C termini as well as of the variable V1/V2 and V3 loops) with the two N-terminal domains of...

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Section: Discussionmentioning

confidence: 99%

Oligomeric Modeling and Electrostatic Analysis of the gp120 Envelope Glycoprotein of Human Immunodeficiency Virus

Kwong

Wyatt

Sattentau

et al. 2000

J Virol

247

196

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“…The availability or the relatively easy access to a number of synthetic porphyrins, the known low toxicity for some of their anionic derivatives (Megnin et al, 1987;Meng et al, 1994) and earlier reports on the screening of porphyrins as antiviral agents against HIV (Ding et al, 1992;Dixon et al, 1992;Neurath et al, 1992;Debnath et al, 1994) prompted us to study anti-Hl.V<l and anti-HIV-2 activities of a large series of anionic porphyrin ligands and their corresponding metallated derivatives. Sulphonated manganese-and iron-porphyrins have been developed in our laboratory for mimicking ligninase (Labat & Meunier, 1989) or chloroperoxidase (Labat & Meunier, 1990), and as biomimetic catalysts for the oxidation of pollutants or drugs (Bernadou et al, 1991;Vidal et al, 1993;Gaggero et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Anti-HIV Activities of Anionic Metalloporphyrins and Related Compounds

Song

Witvrouw

Schols

et al. 1997

Antivir Chem Chemother

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SummaryVarious water-soluble polysulphonated and polycarboxylated porphyrins and some of their metallated derivatives have been prepared and their antiviral properties against human immunodeficiency virus (HIV-1, HIV-2), simian immunodeficiency virus and other viruses are reported. Besides these polyanionic compounds, two new series of porphyrins were included and studied from the perspective of bio-availability modulation: (i) acetylsulphonamido derivatives endowed with weak acidity properties (deprotonation gives the corresponding anionic derivatives in a pH range 4.5-8.5) and (ii) compounds with the anionic charge transiently masked by esterification (acetoxymethyl-and pivaloyloxymethylesters). Among the more active compounds in inhibiting HIV-induced cytopathic effects, the sulphonated and carboxylated porphyrin complexes were found to interact directly with the HIV protein gp 120 and not with the CD4 cellular receptor.

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“…Protoporphyrin (3), hemin (22,25), and other related natural porphyrins and metalloporphyrins (11-13, 16, 25-29) have been shown to have activity against HIV in the micromolar range in such antiviral assays. Sulfonated derivatives of tetraphenylporphyrin have also been shown to be active (16,28,38) as have other selected tetra-arylporphyrins (11,15,16,(26)(27)(28). The mechanisms of action and the stage in the viral life cycle at which the porphyrins exert their inhibitory effects on HIV-1 are not well understood.…”

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confidence: 99%

“…In the V3 loop at least three positively charged and several hydrophobic amino acids are highly conserved at fixed positions. Debnath et al (11) hypothesized that porphyrins containing anionic groups may interact with some of the conserved positively charged sites of the V3 loop, which may induce conformational changes in gp120 leading to the inhibition of virus entry into susceptible cells. There is also evidence that the V3 loop is involved in the interaction of HIV with the alternative receptor Gal-Cer, which appears to be involved in infection of epithelial cells (8,18,49).…”

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confidence: 99%

Inactivation of Human Immunodeficiency Virus Type 1 by Porphyrins

Vzorov¹,

Dixon

Trommel

et al. 2002

Antimicrob Agents Chemother

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We have evaluated the anti-human immunodeficiency virus (HIV) activity of a series of natural and synthetic porphyrins to identify compounds that could potentially be used as microbicides to provide a defense against infection by sexually transmitted virus. For assays we used an epithelial HeLa-CD4 cell line with an integrated long terminal repeat-␤-galactosidase gene. For structure-activity analysis, we divided the porphyrins tested into three classes: (i) natural porphyrins, (ii) metallo-tetraphenylporphyrin tetrasulfonate (metallo-TPPS4) derivatives, and (iii) sulfonated tetra-arylporphyrin derivatives. None of the natural porphyrins studied reduced infection by more than 80% at a concentration of 5 g/ml in these assays. Some metal chelates of TPPS4 were more active, and a number of sulfonated tetra-aryl derivatives showed significantly higher activity. Some of the most active compounds were the sulfonated tetranaphthyl porphyrin (TNapPS), sulfonated tetra-anthracenyl porphyrin (TAnthPS), and sulfonated 2,6-difluoro-meso-tetraphenylporphine [TPP(2,6-F2)S] and its copper chelate [TPP(2,6-F2)S,Cu], which reduced infection by 99, 96, 94, and 96%, respectively. Our observations indicate that at least some of these compounds are virucidal, i.e., that they render the virus noninfectious. The active compounds were found to inhibit binding of the HIV type 1 gp120 to CD4 and also to completely inhibit the ability of Env proteins expressed from recombinant vectors to induce cell fusion with receptor-bearing target cells. These results support the conclusion that modified porphyrins exhibit substantial activity against HIV and that their target is the HIV Env protein.

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Three-Dimensional Structure-Activity Analysis of a Series of Porphyrin Derivatives with Anti-HIV-1 Activity Targeted to the V3 Loop of the gp120 Envelope Glycoprotein of the Human Immunodeficiency Virus Type 1

Cited by 85 publications

References 25 publications

Oligomeric Modeling and Electrostatic Analysis of the gp120 Envelope Glycoprotein of Human Immunodeficiency Virus

Oligomeric Modeling and Electrostatic Analysis of the gp120 Envelope Glycoprotein of Human Immunodeficiency Virus

Anti-HIV Activities of Anionic Metalloporphyrins and Related Compounds

Inactivation of Human Immunodeficiency Virus Type 1 by Porphyrins

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