A structure-based approach to a synthetic vaccine for HIV-1.


:The generation of neutralizing antibodies by peptide immunization is dependent on achieving conformational compatibility between antibodies and native protein. Consequently, approaches are needed for developing conformational mimics of protein neutralization sites. We replace putative main-chain hydrogen bonds (NH --> O=CRNH) with a hydrazone link (N-N=CH-CH(2)CH(2)) and scan constrained peptides for fit with neutralizing monoclonal antibodies (MAbs). To explore this approach, a V3 MAb 58.2 that potently neutralizes T-cell lab-adapted HIV-1(MN) was used to identify a cyclic peptide, [JHIGPGR(Aib)F(D-Ala)GZ]G-NH(2) (loop 5), that binds with >1000-fold higher affinity than the unconstrained peptide. NMR structural studies suggested that loop 5 stabilized beta-turns at GPGR and R(Aib)F(D-Ala) in aqueous solvent implying considerable conformational mimicry of a Fab 58.2 bound V3 peptide determined by X-ray crystallography [Stanfield, R. L. et al. (1999) Structure 142, 131-142]. Rabbit polyclonal antibodies (PAbs) generated to loop 5 but not to the corresponding uncyclized peptide bound the HIV-1(MN) envelope glycoprotein, gp120. When individual rabbit antisera were scanned with linear and cyclic peptides, further animal-to-animal differences in antibody populations were characterized. Loop 5 PAbs that most closely mimicked MAb 58.2 neutralized HIV-1(MN) with similar potency. These results demonstrate the remarkable effect that conformation can have on peptide affinity and immunogenicity and identify an approach that can be used to achieve these results. The implications for synthetic vaccine and HIV-1 vaccine research are discussed.






Cabezas E,Wang M,Parren PW,Stanfield RL,Satterthwait AC




Has Abstract


2000-11-28 00:00:00














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    abstract::We have used resonance energy transfer to study the spatial relationship between Cys-98 of rabbit skeletal troponin C and Cys-133 of rabbit skeletal troponin I in the reconstituted ternary troponin complex. The donor was introduced by labeling either troponin C or troponin I with N-(iodoacetyl)-N'-(5-sulfo-1-naphthyl)...


    pub_type: 杂志文章


    authors: Tao T,Gowell E,Strasburg GM,Gergely J,Leavis PC

    更新日期:1989-07-11 00:00:00

  • Altering the RNase H primer grip of human immunodeficiency virus reverse transcriptase modifies cleavage specificity.

    abstract::Recent crystallographic data suggest that conserved residues in the connection subdomain and C-terminal ribonuclease H (RNase H) domain of human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) contact the nascent DNA primer and modulate the trajectory of the template relative to the RNase H catalytic ce...


    pub_type: 杂志文章


    authors: Rausch JW,Lener D,Miller JT,Julias JG,Hughes SH,Le Grice SF

    更新日期:2002-04-16 00:00:00

  • Probing receptor binding activity of interleukin-8 dimer using a disulfide trap.

    abstract::Interleukin-8 (IL-8), a member of the chemokine superfamily, exists as both monomers and dimers, and mediates its function by binding to neutrophil CXCR1 and CXCR2 receptors that belong to the G protein-coupled receptor class. It is now well established that the monomer functions as a high-affinity ligand, but the bin...


    pub_type: 杂志文章


    authors: Rajarathnam K,Prado GN,Fernando H,Clark-Lewis I,Navarro J

    更新日期:2006-06-27 00:00:00

  • Characterization of synthetic human granulocyte chemotactic protein 2: usage of chemokine receptors CXCR1 and CXCR2 and in vivo inflammatory properties.

    abstract::Human granulocyte chemotactic protein 2 (GCP-2) has originally been isolated from cytokine-stimulated osteosarcoma cells as a chemokine coproduced in minute amounts together with interleukin 8. Human GCP-2 (75 residues) was synthesized on a 0.25-mmol scale using Fmoc chemistry. After disulfide bridge formation and pur...


    pub_type: 杂志文章


    authors: Wuyts A,Van Osselaer N,Haelens A,Samson I,Herdewijn P,Ben-Baruch A,Oppenheim JJ,Proost P,Van Damme J

    更新日期:1997-03-04 00:00:00

  • Endogenous K+/H+ exchange activity in the Sf9 insect cell line.

    abstract::The fluorescent pH indicator 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF) was used to investigate changes in the intracellular pH (pHi) of individual Sf9 cells in response to changes in the composition of the external medium. Under standard conditions, the resting pHi was 0.2-0.3 unit lower than the extracel...


    pub_type: 杂志文章


    authors: Vachon V,Paradis MJ,Marsolais M,Schwartz JL,Laprade R

    更新日期:1995-11-21 00:00:00

  • Tissue factor and its extracellular soluble domain: the relationship between intermolecular association with factor VIIa and enzymatic activity of the complex.

    abstract::We find that the isolated, extracellular domain of tissue factor (TF1-218; sTF) exhibits only 4% of the activity of wild-type transmembrane TF (TF1-263) in an assay that measures the conversion of factor X to Xa by the TF:VIIa complex. Further, the activity of sTF is manifest only when vesicles consisting of phosphati...


    pub_type: 杂志文章


    authors: Waxman E,Ross JB,Laue TM,Guha A,Thiruvikraman SV,Lin TC,Konigsberg WH,Nemerson Y

    更新日期:1992-04-28 00:00:00

  • Replacement of disulfides by amide bonds in the relaxin-like factor (RLF/INSL3) reveals a role for the A11-B10 link in transmembrane signaling.

    abstract::The relaxin-like factor (RLF) also named insulin-like 3 (INSL3) consists of two polypeptide chains linked by two interchain and one intrachain disulfide bond. RLF binds to its receptor (LGR8 also named RXFP2) through the B chain and initiates transmembrane communication by activating the adenylate cyclase through the ...


    pub_type: 杂志文章


    authors: Büllesbach EE,Schwabe C

    更新日期:2012-05-22 00:00:00

  • Reduction of the [2Fe-2S] cluster accompanies formation of the intermediate 9-mercaptodethiobiotin in Escherichia coli biotin synthase.

    abstract::Biotin synthase catalyzes the conversion of dethiobiotin (DTB) to biotin through the oxidative addition of sulfur between two saturated carbon atoms, generating a thiophane ring fused to the existing ureido ring. Biotin synthase is a member of the radical SAM superfamily, composed of enzymes that reductively cleave S-...


    pub_type: 杂志文章


    authors: Taylor AM,Stoll S,Britt RD,Jarrett JT

    更新日期:2011-09-20 00:00:00

  • Affinity selection of chemically modified proteins: role of lysyl residues in the binding of calmodulin to calcineurin.

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    pub_type: 杂志文章


    authors: Manalan AS,Klee CB

    更新日期:1987-03-10 00:00:00

  • Reshaping the Energy Landscape Transforms the Mechanism and Binding Kinetics of DNA Threading Intercalation.

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    pub_type: 杂志文章


    authors: Clark AG,Naufer MN,Westerlund F,Lincoln P,Rouzina I,Paramanathan T,Williams MC

    更新日期:2018-02-06 00:00:00

  • Mutation at active site lysine 212 to arginine uncouples the glycosylase activity from the lyase activity of human endonuclease III.

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    pub_type: 杂志文章


    authors: Liu X,Roy R

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  • Inhibition of apolipoprotein AI gene expression by tumor necrosis factor alpha: roles for MEK/ERK and JNK signaling.

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    pub_type: 杂志文章


    authors: Beers A,Haas MJ,Wong NC,Mooradian AD

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    pub_type: 杂志文章


    authors: Moxley MA,Becker DF

    更新日期:2012-01-10 00:00:00

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    authors: Querfurth HW,Selkoe DJ

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  • Isolation and characterization of bovine factor XII (Hageman factor).

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    pub_type: 杂志文章


    authors: Fujikawa K,Walsh KA,Davie EW

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    pub_type: 杂志文章


    authors: van Meer G,Davoust J,Simons K

    更新日期:1985-07-02 00:00:00

  • Paramecium calmodulin mutants defective in ion channel regulation associate with melittin in the absence of calcium but require it for tertiary collapse.

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    authors: Sorensen BR,Eppel JT,Shea MA

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    pub_type: 杂志文章


    authors: Imamoto Y,Kamikubo H,Harigai M,Shimizu N,Kataoka M

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    pub_type: 杂志文章


    authors: Catalano J,Sadre-Bazzaz K,Amodeo GA,Tong L,McDermott A

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  • A carbon-13 nuclear magnetic resonance study of hyperactive and hypoactive derivatives of luteinizing hormone-releasing hormone: des-Gly-NH210-[DLeu6]LH-RH ethylamide and des-Gly-NH210-[L-Leu6]LH-RH ethylamide.

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    pub_type: 杂志文章


    authors: Deslauriers R,Komoroski RA,Levy GC,Seely JH,Smith IC

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    pub_type: 杂志文章


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    pub_type: 杂志文章


    authors: Callender R,Chen D,Lugtenburg J,Martin C,Rhee KW,Sloan D,Vandersteen R,Yue KT

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    pub_type: 杂志文章


    authors: Rupenyan A,Commandeur J,Groot ML

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    pub_type: 杂志文章


    authors: Bolten M,Niermann M,Eimer W

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    pub_type: 杂志文章


    authors: Schmidt MR,Stansfeld PJ,Tucker SJ,Sansom MS

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    pub_type: 杂志文章


    authors: Kuo HJ,Keene DR,Glanville RW

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    pub_type: 杂志文章


    authors: Wiman K,Claesson L,Rask L,Trägårdh L,Peterson PA

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    pub_type: 杂志文章


    authors: Drewe WF Jr,Dunn MF

    更新日期:1986-05-06 00:00:00

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    pub_type: 杂志文章


    authors: Keith JM,Venkatesan S,Gershowitz A,Moss B

    更新日期:1982-01-19 00:00:00