Potent D-peptide inhibitors of HIV-1 entry

Welch, Brett D.; VanDemark, Andrew P.; Héroux, A.; Hill, Christopher P.; Kay, Michael S.

doi:10.1073/pnas.0708109104

Cited by 238 publications

(247 citation statements)

References 35 publications

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“…The analogous ␣/␤-peptide 4, however, displays only weak affinity for gp41-5, Ͼ10,000-fold lower than that of 3. The modest potency of ␣/␤-peptide 4 in this protein-based assay is similar to that displayed by many small molecules and peptidomimetics in comparable experiments (11)(12)(13)(14)(15)(16)(17).…”

Section: First Generation ␣/␤-Peptide Gp41 Mimic Designs and In Vitromentioning

confidence: 61%

“…The drug enfuvirtide (T-20), a 36-residue ␣-peptide derived from the CHR region, is used clinically as an anti-HIV agent (9,10). However, enfuvirtide is rapidly degraded in vivo and must be administered twice daily in large doses; development of potent fusion inhibitors that resist physiological degradation remains a challenging goal (11)(12)(13)(14)(15)(16)(17). The only non-protein gp41 mimics reported to date that show IC 50 values Ͻ1 M in cell-based assays are multivalent species displaying two or three copes of a phage-derived D-peptide (16).…”

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confidence: 99%

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Structural and biological mimicry of protein surface recognition by α/β-peptide foldamers

Horne

Johnson

Ketas

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

253

269

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Unnatural oligomers that can mimic protein surfaces offer a potentially useful strategy for blocking biomedically important proteinprotein interactions. Here we evaluate an approach based on combining ␣-and ␤-amino acid residues in the context of a polypeptide sequence from the HIV protein gp41, which represents an excellent testbed because of the wealth of available structural and biological information. We show that ␣/␤-peptides can mimic structural and functional properties of a critical gp41 subunit. Physical studies in solution, crystallographic data, and results from cell-fusion and virusinfectivity assays collectively indicate that the gp41-mimetic ␣/␤-peptides effectively block HIV-cell fusion via a mechanism comparable to that of gp41-derived ␣-peptides. An optimized ␣/␤-peptide is far less susceptible to proteolytic degradation than is an analogous ␣-peptide. Our findings show how a two-stage design approach, in which sequence-based ␣3␤ replacements are followed by site-specific backbone rigidification, can lead to physical and biological mimicry of a natural biorecognition process.alpha/beta-peptides ͉ HIV ͉ protein folding ͉ protein-protein interactions I dentification of strategies for interference with specific biopolymer recognition processes constitutes a fundamental challenge. Protein-protein associations are often resistant to inhibition by small molecules because the contact surfaces on the natural partners are large (1). Current clinical approaches to inhibiting proteinprotein interactions that underlie viral infection or aberrant signaling at the cell surface are based on the use of medium-length peptides or proteins (2). It would be valuable to identify alternative sources of antagonists for this type of protein recognition event.Here we show that peptide-like oligomers with unnatural backbones can function as potent antiviral agents by blocking a key protein-protein interaction. The design strategy we employ may prove general for ␣-helix mimicry.The HIV membrane protein gp41 mediates viral envelope-host cell membrane fusion, an essential step in the viral infection cycle. During HIV cell entry, the N-terminal fusion segment of trimeric gp41 inserts into the host cell membrane (3). A profound structural rearrangement of gp41 ensues, driven by formation of an antiparallel six-helix bundle (4-6), which leads to juxtaposition of the viral and host cell membranes. The prehairpin fusion intermediate is composed of three copies of gp41 in an extended conformation. The so-called ''class I'' fusion mechanism used by HIV is common to a variety of enveloped viruses, including those responsible for influenza, Ebola, and SARS (7,8). A number of ␣-peptides based on sequences from the gp41 N-terminal heptad repeat (NHR) domain or C-heptad repeat (CHR) domain (e.g., Fig. 1B, 1 and 2) have been investigated as anti-HIV agents (9, 10). These compounds are thought to act by binding to a gp41 prehairpin intermediate, thereby preventing six-helix bundle formation and subsequent virus-cell fusion. The drug enfu...

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Section: First Generation ␣/␤-Peptide Gp41 Mimic Designs and In Vitromentioning

confidence: 61%

mentioning

confidence: 99%

Structural and biological mimicry of protein surface recognition by α/β-peptide foldamers

Horne

Johnson

Ketas

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

253

269

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“…Such is indeed the case for C34, T20 (4), which spans part of the HR2 region and the sequence downstream (Fig. 1), and several other FI-targeting HR1 or HR2, including peptides, proteins, and small molecules (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency

Ingallinella

Bianchi

Ladwa

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

185

247

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Peptides derived from the heptad repeat 2 (HR2) region of the HIV fusogenic protein gp41 are potent inhibitors of viral infection, and one of them, enfuvirtide, is used for the treatment of therapyexperienced AIDS patients. The mechanism of action of these peptides is binding to a critical intermediate along the virus-cell fusion pathway, and accordingly, increasing the affinity for the intermediate yields more potent inhibitors. We took a different approach, namely to increase the potency of the HR2 peptide inhibitor C34 by targeting it to the cell compartment where fusion occurs, and we show here that a simple, yet powerful way to accomplish this is attachment of a cholesterol group. C34 derivatized with cholesterol (C34-Chol) shows dramatically increased antiviral potency on a panel of primary isolates, with IC 90 values 15-to 300-fold lower than enfuvirtide and the second-generation inhibitor T1249, making C34-Chol the most potent HIV fusion inhibitor to date. Consistent with its anticipated mechanism of action, the antiviral activity of C34-Chol is unusually persistent: washing target cells after incubation with C34-Chol, but before triggering fusion, increases IC 50 only 7-fold, relative to a 400-fold increase observed for C34. Moreover, derivatization with cholesterol extends the half-life of the peptide in vivo. In the mouse, s.c. administration of 3.5 mg/kg C34-Chol yields a plasma concentration 24 h after injection >300-fold higher than the measured IC 90 values. Because the fusion machinery targeted by C34-Chol is similar in several other enveloped viruses, we believe that these findings may be of general utility. antiretroviral drug ͉ enveloped viruses ͉ lipid rafts ͉ peptide therapeutic

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“…We also surmise that isolating the FP stage relevant for inhibition may guide future structural studies. Recent structure-assisted redesign of PIE sequences has yielded optimized versions displaying IC 50 values in the order of pM in neutralization assays [63]. Thus, the first generation of anti-FP D-hexapeptides might also comprise leading platforms for inhibitor optimization in the near future.…”

Section: Ii: Hiv-1 Fusion Inhibition By Targeting the Fusion Peptidementioning

confidence: 99%

Membrane-Transferring Regions of gp41 as Targets for HIV-1 Fusion Inhibition and Viral Neutralization

Huarte

Lorizate²,

Pérez‐Payá³

et al. 2011

CTMC

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Abstract:The fusogenic function of HIV-1 gp41 transmembrane Env subunit relies on two different kinds of structural elements: i) a collapsible ectodomain structure (the hairpin or six-helix bundle) that opens and closes, and ii) two membrane-transferring regions (MTRs), the fusion peptide (FP) and the membrane-proximal external region (MPER), which ensure coupling of hairpin closure to apposition and fusion of cell and viral membranes. The isolation of naturally produced short peptides and neutralizing IgG-s, that interact with FP and MPER, respectively, and block viral infection, suggests that these conserved regions might represent useful targets for clinical intervention.Furthermore, MTR-derived peptides have been shown to be membrane-active. Here, it is discussed the potential use of these molecules and how the analysis of their membrane activity in vitro could contribute to the development of HIV fusion inhibitors and effective immunogens.2

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Potent D-peptide inhibitors of HIV-1 entry

Cited by 238 publications

References 35 publications

Structural and biological mimicry of protein surface recognition by α/β-peptide foldamers

Structural and biological mimicry of protein surface recognition by α/β-peptide foldamers

Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency

Membrane-Transferring Regions of gp41 as Targets for HIV-1 Fusion Inhibition and Viral Neutralization

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