[go: up one dir, main page]

WO2007092457A2 - Ligands de protéines canaux de virus - Google Patents

Ligands de protéines canaux de virus Download PDF

Info

Publication number
WO2007092457A2
WO2007092457A2 PCT/US2007/003169 US2007003169W WO2007092457A2 WO 2007092457 A2 WO2007092457 A2 WO 2007092457A2 US 2007003169 W US2007003169 W US 2007003169W WO 2007092457 A2 WO2007092457 A2 WO 2007092457A2
Authority
WO
WIPO (PCT)
Prior art keywords
protein
antibody
membrane
antibodies
particle
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2007/003169
Other languages
English (en)
Other versions
WO2007092457A3 (fr
Inventor
Tajib Mirzabekov
David Kreimer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MSM PROTEIN TECHNOLOGIES
Original Assignee
MSM PROTEIN TECHNOLOGIES
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by MSM PROTEIN TECHNOLOGIES filed Critical MSM PROTEIN TECHNOLOGIES
Publication of WO2007092457A2 publication Critical patent/WO2007092457A2/fr
Publication of WO2007092457A3 publication Critical patent/WO2007092457A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies

Definitions

  • trans-membrane proteins proteins that are particularly important targets. These proteins typically are involved in vital functions of cells and viruses, and therefore selectively affecting them often brings a desirable outcome in a patient's health.
  • a distinctive feature of trans-membrane proteins is a domain or domains that span the lipid bilayer of a biological membrane, whereas only a portion of such a protein is typically present on the surface of a cell or viral particle.
  • a ligand that binds to such an exposed domain on the surface of a cell or virus might change the protein's function; such a ligand could have therefore a great pharmaceutical potential.
  • Search for ligands that bind such exposed, external domains of membrane proteins remains to be extremely laborious and inefficient process.
  • transmembrane protein such as cells, viral particles or cellular membranes, or with peptide fragments of a trans-membrane protein
  • library screening in which one tries to isolate from a library containing a large number of potential ligands those components that bind to a preparation of trans-membrane protein, such as cells, viral particles or cellular membranes, or to peptide fragments of a trans-membrane protein.
  • fragments of membrane proteins has proven inefficient because such fragments generally do not maintain native conformation, and even when a ligand that bind such a peptide is discovered, such a ligand often is unable to exert a desirable change upon the function of a membrane protein.
  • MPLs Magnetic Proteoliposomes
  • MPLs allow one to purify certain membrane proteins in their native, functional conformation, and can stabilize the protein in proper orientation and at high concentration on the surface of easy-to-handle magnetic beads by way of peptide or protein "tags" engineered on the protein.
  • tags can stearically hinder proteins in MPLs and can thereby alter the protein into a non-native configuration.
  • Antibodies and other ligands directed against non-natively configured proteins can render the ligand ineffective in modulating the membrane spanning protein in its native state on a virus. Therefore, while MPLs have been proven useful in human antibody development using both transgenic mouse immunization and by selection of antibodies from phage display libraries, there is an ongoing need for improved methods for producing antibodies and other ligands that can affect membrane-spanning proteins.
  • multimeric membrane spanning proteins can be expressed in a MPL without having tags on all monomers.
  • a complex comprising a multimeric membrane spanning protein can be successfully expressed in a MPL without the alterations in configuration that can render prior art MPLs ineffective.
  • Manufacture of such complexes can be achieved using expression vectors that provide tags to only a selected number of monomers.
  • proteins having 4 monomers one can co-transfect cells with: (1) a vector that encodes a monomer with a tag and (2) a vector that encodes the monomer without a tag.
  • the resultant multimeric protein can be assembled from a mixture of tagged and un-tagged monomers, thereby producing a "hetero-multimeric" protein.
  • the hetero-multimeric protein is expressed in the form of a MPL, the MPL is termed a "hetero-multimeric MPL" or "HMPL.”
  • HMPL hetero-multimeric MPL
  • the protein is less prone to taking on a non-native conformation.
  • hetero-multimeric proteins can be easily captured by a capture reagent (e.g., antibody) designed to recognize a tag- Once a capture antibody recognizes one tag on a hetero-multimeric protein, the entire protein complex can be then formed into an HMPL.
  • a capture reagent e.g., antibody
  • HMPLs can dramatically reduce the time for selection of ligands from various libraries, such as chemical library, phage, aptamer, shpigelmer, nanobody, antibody fragment, scFv, minibody, anticalin or other protein scaffold library, cell library, and any other library.
  • heteromeric transmembrane protein complexes can be made with fewer than a stoichiometric numbers of tags. In this way, there is less interference of the tag(s) with the proper orientation and structure of the multimeric complex.
  • influenza protein M2 can be desirably used.
  • the activity of M2 can be decreased, thereby decreasing infectivity and the mobidity and mortality associated with influenza pandemics.
  • antibodies can be directed at a highly conserved "box" structure of the M2 multimer can improve efficacy. ' Because the box structure is highly conserved and is necessary for formation of functional channels, antibodies directed against this structure are less sensitive to mutations in M2. Antibodies against M2 can bind to the box structure and can block the channel in M2, thereby decreasing the ability of M2 to promote infection. Even mutations that would render viruses drug-resistant need not render the mutant resistant to an anti-M2 antibody.
  • FIGS. Ia - Ic depict the structure of the M2 protein.
  • FIG Ia depicts the M2 protein comprised of tag-carrying and unmodified polypeptide chains of present invention.
  • FIG. Ib depicts a side view the extra-cellular domain (ectodomain) of the M2 protein with the box structure.
  • FIG. Ic depicts a top view of the extra-cellular domain (ectodomain) of the M2 protein having a box structure.
  • FIG. 2 schematically depicts a HMPL particle of this invention that carries on its surface the M2 protein molecules of present invention having the box structure of this invention in the native conformation in a reconstituted lipid bilayer.
  • M2 protein of influenza A virus is a proton channel, and is genetically linked to another viral protein, Ml. Therefore, among three major antigens of Influenza A, virus hemagglutinin (HA), neuraminidase (NA), both of which have high level of point mutations and antigenic shifts, a third, the M2 protein, has a low level of sequence variation.
  • HA virus hemagglutinin
  • NA neuraminidase
  • the M2 protein is a proton-selective ion channel with pH-inducible activity; it is involved in virus uncoating in the endosome, i.e., in viral fusion and infection, and in virus maturation in trans-Golgi network.
  • the M2 protein is expressed at the plasma membrane of virus-infected cells and is also exposed on the viral surface. Table 1 below illustrates the low level of sequence variation observed in various strains of M2 since 1918. The M2 sequences of viruses that caused pandemics of 1918,
  • One series of embodiments of present invention includes HMPLs that carry the M2 protein of influenza A virus on their surface.
  • Another embodiment of present invention includes antibody-ligands that can bind the M2 protein exposed on the surface of these preparations.
  • the M2 protein from influenza A virus is an integral membrane protein comprised of four identical, disulfide-1 inked, 97 amino acids polypeptide chains, each containing a TM helix.
  • the M2 protein forms proton-selective channel that is essential to viral function and is the target of the drug Amantadine and similar agents.
  • M2 is highly conserved. Rare mutations in M2 however do occur, and that renders Amantadine inefficient in treatment of several strains of viruses.
  • Amantadine and similar agents are small molecules whose binding site changes substantially upon such mutations, the binding of antibodies that would have significantly larger volume can be affected by such mutations to a significantly lesser extent. Therefore, the M2 protein appears to be a very attractive target for development of human therapeutic antibodies and universal anti- influenza vaccines.
  • some embodiments of the present invention include the use of MPLs that can maintain the native "box structure" of M2.
  • This box structure is a portion of the M2 protein that can be maintained properly protruded into external space from the area of transmembrane domain by maintaining overall native conformation of the protein.
  • the structure of this portion is presumably constrained by disulfide bonds formed by Cys-17 and Cys-19 and intermolecular interactions between tetramer subunits and interactions with the lipid membrane.
  • Residues 24, 23 and 22 adjacent to the transmembrane (TM)-domain are engaged in a defined 3-D structure that most probably extend farther away due to the inter-chain Cystines at positions 19 and 17.
  • the ectodomain fragment structure is thus vastly different from that presented in the bacterially synthesized water-soluble fusion proteins used for vaccine development by the prior art. It is likely that in the 1-24 fragment of the extra-cellular peptide, only first approximately 10 amino acids (unrelated to the channel functions) remain unstructured in the native M2 tetramer. Typically, when N-terminal peptides (20-30 amino acid (aa) long) of trans-membrane proteins such as GPCRs are used for immunization, antibodies that arise bind only to a small portion at the very end of these peptides.
  • yet another embodiment of the present invention describes selection of ligands that bind to the external portion of the M2 protein that maintains its native conformation via numerous interactions within transmembrane domains and the box structure.
  • antibodies can be fully humanized to decrease the likelihood of adverse immunological reactions to the antibody.
  • Such fully human antibodies of the present invention can bind the native functional M2 channel and some can inactivate it akin to the Amantadine action. Additionally, they can induce an antibody activating body's immune response (ADCC, CDC) against the influenza virus.
  • ADCC antibody activating body's immune response
  • our technologies can allow the identification of antibodies able to bind to the M2 channel at both, neutral and low pH.
  • the therapeutic antibodies might be of a broad use because of long blood circulation time (around 1 month).
  • paramagnetic particles for example M-280 Tosylactivated DynabeadsTM produced by Dynal Biotech Inc. are chemically derivatized with a capture agent, using the protocol provided by the Dynal Biotech Inc.
  • a capture agent can be an antibody that is capable of selective binding a respective tag, or streptavidin that can bind a known peptide tag; either of the tags can be attached at the C-terminus of a given membrane protein.
  • a given membrane protein can be over-expressed in a mammalian cell by transfecting, by using for example a GenePORTERTM transfection reagent and protocol (Gelantis), a line of mammalian cells (can be purchased at ATCC) with a vector (for example, pcDNA3.1, from Invitrogen) carrying the gene of the protein having an appropriate peptide tag at the C-terminus and genes that provide an antibiotic resistance to the cells.
  • a vector for example, pcDNA3.1, from Invitrogen
  • cells can be transfected with vectors that encode tagged monomers and other vectors that encode un-tagged monomers.
  • a single vector having two or more expression cassettes (one cassette having a sequence encoding a tagged monomer and another cassette encoding a untagged monomer) can be used.
  • a mixture of tagged and untagged monomers can be produced, that when associated with each other, form a hetero-multimeric protein complex.
  • Antibiotic resistance for example, resistance to gentamycin (GeneticinTM; G418), the feature acquired concomitantly with the capacity to over-express the membrane protein, can be used for selecting over-expressing cells that survive in the presence of added the antibiotic.
  • cells that over-express the membrane protein can be harvested, and the membranes of the cells can be solubilized in a mixture of detergents and lipids (e.g. phosphatidylcholine, phosphatidylserine, phosphatidethanolamine, or lipid mixtures isolated form tissues or plants).
  • a mixture of detergents and lipids e.g. phosphatidylcholine, phosphatidylserine, phosphatidethanolamine, or lipid mixtures isolated form tissues or plants.
  • solublized membrane solution can be clarified by centrifugation solubilization and containing the membrane protein of interest along with numerous other contaminating proteins, can be mixed with the beads carrying a capture agent capable of binding the tag on the protein.
  • washing the beads can remove contaminants.
  • a magnet can be used to hold beads within a vessel (e.g., tube) and washing solutions can be added, to carry away non-bound materials, including contaminants.
  • the beads retaining the protein of our interest in the desirable orientation i.e., the extracellular portion is exposed on the surface of the bead
  • MPLs are provided that carry the M2 protein on their surface in the native, tetrameric state.
  • An important feature of the M2 protein is the presence of the box structure that is desirably maintained using special care to obtain MPLs that have the box structure in the proper, native configuration.
  • Such MPLs are desirable because antibodies and other ligands made that bind to M2 proteins having box structures in their native configuration are better suited for binding with M2 in in vivo conditions. Therefore, such antibodies and other ligands can be better reagents for affecting the function of M2.
  • Ligands can be then selected from a library, such as phage antibody library or can be obtained by immunization and selection of an antibody from an antibody pool.
  • FIG. Ia schematically displays the structure of the M2 protein of present invention 1100.
  • the native protein is comprised of four identical polypeptide chains 1000.
  • Each polypeptide chain 1000 contains an ectodomain 1001, a transmembrane domain 1002 and a cytoplasmic domain 1003. In some embodiments 1110, it can be desirable to add tag
  • Tag 1004 can be used to attach the protein
  • a magnetic bead for constructing MPLs and/or naked particles of the present invention.
  • an antibody against a cytoplasmic portion 1003 of the protein can serve for retention of the protein in the correct orientation on the surface of the particles.
  • Lipid molecules 1102 are depicted as stabilizing the heterotetramer. Additionally, disulfide bridges 1101 are shown
  • MPLs can be manufactured utilizing the hetero-tetramer protein.
  • each of four chains have three identical domains: an ectodomain 1001 of 24 amino acids; a trans-membrane domain 1002 of 19 amino acids; and a cytoplasm domain 1003 of 54 amino acids.
  • one, two or three chains carry tag 1004.
  • Such a hetero-tetramer protein can be obtained by doing transfection with a mixture of two vectors; one vector encoding an unmodified sequence and one other vector encoding sequence with the tag.
  • a single vector can contain an open reading frame encoding a native protein and an open reading frame encoding a tagged protein.
  • the single vector can produce both native protein and tagged protein. Regardless of how the tagged and native proteins are formed, once made, the monomers can then assemble into the tetrameric form.
  • the structure is termed herein a "hetero-tetramer.”
  • a native structure of the protein with little or no distortion of the M2 protein structure can be achieved.
  • the native box structure is maintained.
  • the structure of such hetero-tetramer is shown with lipids 1102 that surround trans-membrane domain 1002. Disulfide bridges 1101 are also shown that link the chains of the protein together to form the typical "box" structure.
  • FIGS. Ib and Ic depict side and top views, respectively, of M2 protein in a HMPL of this invention.
  • FIG Ib shows the extra-cellular domain (ectodomain) 1103 of the M2 protein with the box structure 1102 that is adjacent to the trans-membrane domain 1002 of the M2 protein.
  • Amino acids 1121 involved in the formation of the box are depicted in white, while amino acids 1111 involved in less structured portion of the ectodomain 1103 are shown in black.
  • disulfide bridges 1101 that link the chains of the protein thus forming box structure 1102. Box 1102 leads to the entrance of the channel formed by trans-membrane portions 1002 surrounded by lipids 1104.
  • FIG Ic is a top view of the extra-cellular domain of M2.
  • Transmembrane domains 1002, "box" amino acids 1121 and “non-box” amino acids 1111 are depicted as for FIG Ib above.
  • Disulfide bridges 1101 are shown in an approximately tetrahedral structure, thereby identifying the "box.” Protons flow along arrow into channel 1311.
  • the density of the capture agent on the surface of the bead and the nature of the tag can be selected. Complete coverage of the bead with the capture agent could result in a distortion arising due to immobilization of more than one tag of the same tetramer that might propagate through the body of the protein's trans-membrane domain into the box area. Therefore, using a hetero-tetramer can help avoid the distortion.
  • Cys-17 and Cys-19 are engaged in inter-chain disulfide bonds. It can be desirable to avoid reducing conditions and reducing agents such as beta-mercaptoethanol and DTT, or use them only at very low concentrations.
  • FIG. 2 depicts an MPL particle 2001 of this invention carrying the hetero- tetramer M2 protein 1100 on its surface.
  • Paramagnetic particle 2002 is derivatized with a capture agent 2003 capable of binding tag 1004.
  • a lipid bilayer comprised from lipids 2004 can cover the whole particle, as schematically shown with lines 2005.
  • MPLs or HMPLs carrying the M2 protein in the native state can be used to raise mouse antibodies against the ectodomain of the protein. These mouse antibodies can be used for demonstrating the therapeutic activity of the anti-M2 preparations in mouse model.
  • mice having a complete human immune system
  • MPLs carrying the M2 protein By immunizing humanized mice (mice having a complete human immune system) with MPLs carrying the M2 protein in the native state, fully humanized anti-M2 antibodies that bind the ectodomain of the protein can be obtained. These antibodies can be used for therapeutic purposes in humans.
  • MPLs carrying M2 in its native state as well as naked particles can be used for successful selection of anti-M2 ligands.
  • the presence of antibodies that bind the ectodomain of the M2 protein can be determined using MPLs or naked particles. Binding of an antibody to such a particle can be determined using a fluorescently labeled secondary antibody directed at the primary M2 antibody. This secondary antibody binds to anti-M2 antibody bound to the particle; this binding can be visualized using FACS or fluorescence microscopic methods. V. Antibody Function
  • Some antibodies obtained via immunization or from a library may only affect the development of influenza A viral infection indirectly by binding to the M2 protein expressed on the surface of infected cells, and some antibodies can directly affect the viral cycle by inhibiting channel function and other functions via direct binding to the M2 protein on the viral surface.
  • Functional antibodies that bind to or in proximity to the box structure can be more desirable than those that bind a portion of the protein that is distant from the box structure.
  • the box structure leading to the channel can be affected by the antibody binding and such binding can change the conformation of the channel; thereby inhibiting its function.
  • an antibody can hinder entry of ions into the channel through its size.
  • antibodies produced using MPLs of this invention can be effective at inhibiting the function of M2.
  • Such loss of function can be useful important for halting the infection.
  • a functional antibody can act via a mechanism similar to that of Amantadine. It can be desirable to use additional stringency criterion in selection of antibodies with channel inhibitory capacity. These antibodies are desirably stable at acidic pH in order to be able to prevent viral uncoating in the endosome.
  • Antibodies that bind the M2 ectodomain can directly inhibit channel activity.
  • the function can be demonstrated in patch clamp experiment in which membrane potential in cells expressing the M2 protein is measured as the function of the presence of such an antibody.
  • fluorescent probes sensitive to membrane potential can be used for identifying the functional effect of a given antibody.
  • MPLs of present invention can be used for selection of other small molecules from chemical libraries that can bind to the ectodomain or trans-membrane domain and can inhibit ion flow through channels. Such molecules can be of great pharmaceutical significance because numerous viral strains have evolved that escape inhibitory effect of Amantadine.
  • MPLs of this invention Upon exposure of MPLs of this invention to a solution containing a small molecule ligand, MPLs are washed using magnetic force for their retention, and then are subjected to denaturing conditions in order to release bound molecules. Because each MPL can carry on its surface up to 100,000 molecules of the M2 protein, there is enough material even in very small amounts of MPLs for identification of bound small molecules by using mass-spectrometry.
  • Vaccines Preparations in which the M2 protein is presented in its native state can induce much superior immune responses to those of the prior art.
  • liposomal formulations of functional M2 channels can be used for intranasal vaccination.
  • other virus proteins can be used for antibody and vaccine manufacture.
  • Channel proteins are present in several other viruses, such as HIV.
  • the use of preparations disclosed in this invention for the M2 channel can be expanded to immunization and selection of ligands that bind to viral channel proteins of other viruses. Functional ligands that inhibit channel function in these viruses can be used for treatment of these viral infections.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Ceramic Engineering (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

Les ligands qui exercent des effets biologiques sur des virus par liaison à leurs composants protéiques transmembranaires tel que le canal membranaire M2 dans le virus de la grippe, présentent une grande importance pharmacologique. L'invention concerne des procédés de fabrication de particules qui portent une telle protéine canal à leur surface, orientée de la même façon que dans des membranes virales et cellulaires. L'invention concerne également des procédés de production d'anticorps qui se lient à la protéine canal dans les particules ainsi que l'utilisation desdits anticorps pour le traitement d'infections.
PCT/US2007/003169 2006-02-06 2007-02-05 Ligands de protéines canaux de virus Ceased WO2007092457A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US76571206P 2006-02-06 2006-02-06
US60/765,712 2006-02-06

Publications (2)

Publication Number Publication Date
WO2007092457A2 true WO2007092457A2 (fr) 2007-08-16
WO2007092457A3 WO2007092457A3 (fr) 2008-04-10

Family

ID=38345753

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2007/003169 Ceased WO2007092457A2 (fr) 2006-02-06 2007-02-05 Ligands de protéines canaux de virus

Country Status (1)

Country Link
WO (1) WO2007092457A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7893108B2 (en) 2004-07-14 2011-02-22 President And Fellows Of Harvard College Antiviral methods and compositions

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE365539T1 (de) * 1999-12-30 2007-07-15 Dana Farber Cancer Inst Inc Proteoliposomen, die ein integral membranprotein mit einer oder memhreren transmembrandomänen enthalten

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7893108B2 (en) 2004-07-14 2011-02-22 President And Fellows Of Harvard College Antiviral methods and compositions

Also Published As

Publication number Publication date
WO2007092457A3 (fr) 2008-04-10

Similar Documents

Publication Publication Date Title
Boyoglu-Barnum et al. Quadrivalent influenza nanoparticle vaccines induce broad protection
Meher et al. Membrane cholesterol modulates oligomeric status and peptide-membrane interaction of severe acute respiratory syndrome coronavirus fusion peptide
Ekiert et al. A highly conserved neutralizing epitope on group 2 influenza A viruses
Barrett et al. Viral membrane fusion and the transmembrane domain
TWI618715B (zh) 流感病毒疫苗及其用途
Ekiert et al. Antibody recognition of a highly conserved influenza virus epitope
WO2021178971A1 (fr) Vaccins contre le sras-cov-2 et d'autres coronavirus
Mahajan et al. NMR structures and localization of the potential fusion peptides and the pre-transmembrane region of SARS-CoV: Implications in membrane fusion
Sun et al. Internalization and fusion mechanism of vesicular stomatitis virus and related rhabdoviruses
Monso et al. Influence of conjugation chemistry and B epitope orientation on the immune response of branched peptide antigens
Liao et al. Tryptophan-dependent membrane interaction and heteromerization with the internal fusion peptide by the membrane proximal external region of SARS-CoV spike protein
Düzgüneş et al. Inhibition of viral membrane fusion by peptides and approaches to peptide design
Jackman Antiviral peptide engineering for targeting membrane-enveloped viruses: Recent progress and future directions
Figueira et al. Structure–Stability–Function Mechanistic Links in the Anti-Measles Virus Action of Tocopherol-Derivatized Peptide Nanoparticles
Birtles et al. Identifying distinct structural features of the SARS-CoV-2 spike protein fusion domain essential for membrane interaction
CA3114870A1 (fr) Mutations stabilisant l'enveloppe du vih-1
Gomara et al. Peptide assembly on the membrane determines the HIV-1 inhibitory activity of dual-targeting fusion inhibitor peptides
Ranaweera et al. The stabilities of the soluble ectodomain and fusion peptide hairpins of the influenza virus hemagglutinin subunit II protein are positively correlated with membrane fusion
Dai et al. Conditional trimerization and lytic activity of HIV-1 gp41 variants containing the membrane-associated segments
Niort et al. Cholesterol and Ceramide Facilitate Membrane Fusion Mediated by the Fusion Peptide of the SARS-CoV-2 Spike Protein
Wholey et al. Site-specific and stable conjugation of the SARS-CoV-2 receptor-binding domain to liposomes in the absence of any other adjuvants elicits potent neutralizing antibodies in BALB/c mice
Li et al. Hemagglutinin stability determines influenza A virus susceptibility to a broad-spectrum fusion inhibitor Arbidol
Nemésio et al. Membrane interacting regions of Dengue virus NS2A protein
Guillén et al. A second SARS-CoV S2 glycoprotein internal membrane-active peptide. Biophysical characterization and membrane interaction
Kwon et al. The influenza M2 ectodomain regulates the conformational equilibria of the transmembrane proton channel: insights from solid-state nuclear magnetic resonance

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07763349

Country of ref document: EP

Kind code of ref document: A2