US20080015145A1 - Mimotope receptors and inhibitors for platelet-platelet and platelet-endothelium interactions - Google Patents

Mimotope receptors and inhibitors for platelet-platelet and platelet-endothelium interactions Download PDF

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US20080015145A1
US20080015145A1 US11/484,364 US48436406A US2008015145A1 US 20080015145 A1 US20080015145 A1 US 20080015145A1 US 48436406 A US48436406 A US 48436406A US 2008015145 A1 US2008015145 A1 US 2008015145A1
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receptor
platelet
peptide
mimotope
ligand
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US11/484,364
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Maria Gyongyossy-Issa
Dana V. Devine
Iren Constantinescu
William Campbell
Carlos del Carpio Munoz
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Canadian Blood Services
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Individual
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Priority to US11/484,364 priority Critical patent/US20080015145A1/en
Assigned to CANADIAN BLOOD SERVICES, INC. reassignment CANADIAN BLOOD SERVICES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DEVINE, DANA V., CONSTANTINESCU, IREN, GYONGYOSSY-ISSA, MARIA I.C., CAMPBELL, WILLIAM, DEL CARPIO MUNOZ, CARLOS A.
Priority to PCT/CA2006/001699 priority patent/WO2008006189A1/en
Priority to EP12154918A priority patent/EP2471812A1/en
Priority to EP06790853A priority patent/EP2046827A4/en
Priority to CA002657310A priority patent/CA2657310A1/en
Publication of US20080015145A1 publication Critical patent/US20080015145A1/en
Priority to US12/546,811 priority patent/US7919465B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • 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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/56—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates generally to mimotopes and, in particular, to mimotopes for mimicking the receptor and inhibitor functionality of platelets.
  • Mimotopes are molecules that mimic the function of other, naturally-occurring molecules by virtue of having the same shape (topography) and size as the naturally-occurring molecules that they are mimicking.
  • a method for determining mimotopes is described in U.S. Pat. No. 4,833,092 (Geysen).
  • a natural ligand has a particular shape and size that enables it to bind to a natural receptor.
  • a mimotope ligand is a molecule that mimics the shape of the natural ligand and thus mimics its functional ability to bind to a natural receptor, as shown in FIG. 1 b .
  • a mimotope ligand is a molecule that is the topographical equivalent of a natural ligand (at least in terms of their binding surfaces) so as to be complementary to a particular receptor of interest.
  • ligand mimics are known in the art, which are used primarily as inhibitors or blockers, e.g. U.S. Pat. No. 4,550,163 (Voss et al.) entitled “Ligand analog-irreversible enzyme inhibitor conjugates” and U.S. Pat. No. 6,139,832 (Li et al.) entitled “Leukocyte adhesion inhibitor-1 (LAI-1) Polypeptides”. Small peptides are also known as protein mimetics (see, e.g. Wrighton et al., “Small Peptides as Potent Mimetics of the Protein Hormone Erythropoietin” in Science (1996 July 26;273 (5274):458-64).
  • Mimetics of polypeptides used to detect antibodies are described in U.S. Pat. No. 6,858,210 (Marquis et al.).
  • Peptide mimics for backbone-to-backbone or backbone-to-chain cyclizations are described in U.S. Pat. No. 6,706,862 (Hornik).
  • mimotopes are also known as inhibitors of platelet adhesion and aggregation, such as described in U.S. Pat. No. 5,114,842 (Plow et al.) entitled “Peptides and Antibodies that Inhibit Platelet Adhesions”.
  • Plow et al. teach a polypeptide analog capable of immunologically mimicking a linear hGPIIb antigenic determinant expressed when platelet-associated GPIIb-IIIa binds fibrinogen.
  • one object of the present invention is to provide more pharmacologically compatible mimotope inhibitors for a new class of antithrombotic drugs.
  • This invention relates to the creation of peptide mimics of platelet integrins and their ligands.
  • Short peptides usually between 10-20 mer, are designed to provide shapes complementary to either the receptor or the ligand.
  • a shape that mimics an integrin receptor's binding surface can be used to mimic the integrin receptor's binding function.
  • Attached to a supporting surface of a carrier, such a peptide can behave as a receptor.
  • As a free molecule, such a peptide can attach to the ligand, preventing it from accessing the receptor, thus acting as an inhibitor of the receptor-ligand interaction.
  • a peptide that mimics the ligand's binding surface for the receptor will compete with the ligand and reduce its access to the receptor, thus also acting an inhibitor of receptor-ligand interaction.
  • Such peptides may have, but are not obligated to have, sequence similarities to their parent proteins: they just need to have a complementary shape with sufficient binding affinity to attach to their counterpart in the receptor-ligand pair. Consequently, such peptides may be composed of L or D amino acids, although the D amino acids are preferred as these resist proteolytic degradation.
  • one aspect of the present invention provides a mimotope receptor comprising a peptide that mimics the shape and function of a natural receptor, thus providing a synthetic binding site for ligands.
  • the mimotope receptor inhibits ligand-receptor interaction, e.g. acts as an antithrombotic in the context of platelet-platelet or platelet-endothelium interactions.
  • the mimotope receptor acts as a synthetic binding site, e.g. the carrier and mimotope receptor together function as a synthetic platelet.
  • Another aspect of the present invention provides a mimotope ligand comprising a peptide that mimics a natural ligand capable of binding to a receptor to thus inhibit ligand-receptor interaction, wherein the peptide is a D-peptide. Since the peptide is dextrorotary, it resists proteolytic degradation and thus forms the basis for a new class of antithrombotic drugs.
  • a mimotope ligand comprising a peptide that mimics a natural ligand capable of binding to a receptor to thus inhibit ligand-receptor interaction, wherein the peptide is attached to a carrier. Since the peptide is attached to a carrier, it resists excretion, again forming the basis for a new class of antithrombotic drugs. In one embodiment, the peptide is also dextrorotary to resist proteolytic degradation.
  • a further aspect of the present invention provides a synthetic platelet comprising a carrier and a receptor mimic attached to the carrier, the receptor mimic mimicking a shape and size of a binding site of a natural receptor on a natural platelet.
  • a synthetic or artificial platelet (or “platelet substitute”) would have virtually limitless shelf life and would not require disease screening prior to transfusion, thereby providing a solution to the perpetual platelet shortages, as well as the safety and storage issues associated with natural blood platelets.
  • FIG. 1 a is a schematic illustration of a ligand-receptor interaction between a natural ligand and a natural receptor
  • FIG. 1 b is a schematic illustration of a ligand mimic binding to a natural receptor, thus acting as an inhibitor of the ligand-receptor interaction, as is known in the art;
  • FIG. 1 c is a schematic illustration of a peptide-based material that mimics the function of a receptor such as, for example, an integrin receptor on the surface of a platelet and further showing a natural ligand binding to the receptor mimic;
  • a receptor such as, for example, an integrin receptor on the surface of a platelet and further showing a natural ligand binding to the receptor mimic;
  • FIG. 2 a is a schematic illustration of a peptide-based material that, by binding to the ligand like a receptor, can inhibit receptor-ligand interactions;
  • FIG. 2 b is a schematic illustration of a peptide-based material that, when attached to a large carrier at low coupling ratios, binds to the ligand to thus mimic a receptor, thereby providing a specific, quasi-monovalent inhibitory function such as, for example, functioning as an antithrombotic in the case of platelet-endothelium and platelet-platelet interactions;
  • FIG. 2 c is a schematic illustration of a peptide-based material that, when coupled to a large carrier at high coupling ratios, provides specific multivalent attachment possibilities, thus mimicking a receptor that is capable of binding multiple ligands;
  • FIG. 3 a is a schematic illustration of a peptide-based material comprising D-amino acids that can bind into an integrin receptor to thereby inhibit its ligand-binding function;
  • FIG. 3 b is a schematic illustration of a peptide-based material that, when attached to a large carrier at a low coupling ratio, binds to the receptor, mimicking a ligand, and thus providing a specific, quasi-monovalent inhibitory function such as, for example, functioning as an antithrombotic in the case of platelet-endothelium or platelet-platelet interactions;
  • FIG. 4 shows a 3 D computer model of a parent protein used for finding positions of particular sequences to enable the position to be related to potential vWf-GPIb interaction sites;
  • FIG. 5 shows four cellulose membranes to which peptides were attached and which were then probed with purified GPIb in order to identify sequences of D-amino acids which potentially inhibit the GPIb-vWf interaction;
  • FIG. 6 shows the confirmatory structural results of 3D computer modeling of the interaction between a D-peptide and vWf;
  • FIG. 7 shows schematically how surface plasmon resonance in a Biacore machine can be used to validate that the peptides can act as receptors/binding partners
  • FIG. 8 shows a Langmuir binding analysis used to determine the KD of the binding interaction between the peptide and fibrinogen.
  • embodiments of the present invention provide mimotope receptors and inhibitors that employ peptide mimics for mimicking the shape and function of natural receptors and ligands, thus providing synthetic binding sites for ligands and receptors.
  • Receptor mimics can be attached to carriers, such as liposomes, to act as synthetic platelets, for example, by providing binding sites for binding to other (natural or synthetic) platelets or to the endothelium.
  • Mimotope inhibitors can act as antithrombotics by inhibiting platelet-platelet and/or platelet-endothelium interactions.
  • a peptide-based material can be used as a mimotope to mimic the form/shape (and thus the function) of a receptor.
  • the mimotope receptor (receptor mimic) can bind to a ligand to inhibit binding of the ligand to a natural receptor.
  • the mimotope receptor can be a peptide-based material that mimics an adhesion receptor or integrin on the surface of a platelet-like carrier like a liposome, preferably a cross-linked liposome.
  • an integrin, integrin receptor or (simply) receptor shall be used synonymously in the present specification to mean a molecule, such as a peptide or protein, on the surface of the platelet or carrier that selectively binds a specific molecule known as a ligand.
  • a peptide-based material can be used as a receptor mimetic to bind to the ligand like a receptor, thus inhibiting receptor-ligand interactions.
  • the mimotope receptor can be a “free” (unattached) peptide that has a shape/topology like that of a natural receptor so that it binds “preemptively” to ligands, thus preventing the ligands from binding to their natural receptors.
  • These unattached, “free” receptor mimics thus act as inhibitors or blockers of the natural receptor-ligand interactions.
  • these mimotope receptors can be made of peptides that mimic the adhesion receptors or integrins of platelets. In the context of platelets, therefore, these unattached, “free” peptides would have an antithrombotic effect by binding to ligands and/or other factors, thus inhibiting normal platelet-platelet or platelet-endothelium adhesion.
  • the mimotope receptor shown in FIG. 2 a could be a peptide that mimics an integrin of a platelet.
  • the peptide mimic could be shaped to bind to a ligand such as one of the active sites of a von Willebrand factor (vWf) protein.
  • vWf von Willebrand factor
  • vWf monomer which is a ⁇ 2050 amino acid protein
  • A1 domain for example, binds to the platelet GPIB receptor.
  • the C1 domain binds to platelet integrin ⁇ IIb ⁇ 3 when activated.
  • the mimotope receptor could be a peptide that mimics the shape and structure of the binding site of platelet GPIb-receptor by binding preemptively to the A1 domain of the vWf monomer.
  • the mimotope receptor could be a peptide that mimics the shape and structure of the binding site of platelet integrin ⁇ II ⁇ 3 .
  • the mimotope receptor shown in FIG. 2 a could also be used to inhibit platelet-endothelium interaction by binding to the corresponding natural ligand that normally promotes adhesion of platelets to the vascular endothelial cells such as, for example, von Willebrand factor.
  • the vascular endothelial cells such as, for example, von Willebrand factor.
  • circulating platelets do not adhere to normal endothelium because platelet adhesion requires endothelial cell secretion of von Willebrand factor, which is found in the vessel wall and in plasma.
  • the vWf protein binds during platelet adhesion to a glycoprotein receptor of the platelet surface membrane (glycoprotein Ib).
  • platelet-endothelium interaction can be inhibited by a mimotope receptor (peptide mimic) that binds preemptively to one of the active sites of the vWf protein to thus obstruct subsequent binding to that particular site on the vWf protein.
  • mimotope receptor peptide mimic
  • a peptide-based material can also be attached to a large carrier at low coupling ratios for providing monovalent or quasi-monovalent inhibitory functions.
  • This mimotope is thus a monovalent receptor mimic which, whether attached to a carrier or not, can bind to a corresponding ligand, thus inhibiting receptor-ligand interactions.
  • this mimotope provides a specific, quasi-monovalent inhibitory function that can be used, for example, as an inhibitor of platelet-platelet and platelet-endothelium interactions. This mimotope could thus be used as an antithrombotic.
  • a peptide-based material can be coupled to a large carrier at high coupling ratios to provide specific, multivalent attachment possibilities, i.e. the synthetic receptor can simultaneously bind a plurality of ligands.
  • the mimotope mimics a multivalent receptor and thus can form the basis of a synthetic platelet substitute.
  • platelets are anuclear and discoid spherules (“flattened ellipsoids”) that measure approximately 1.3-3.0 microns in diameter. Platelets adhere to each other via adhesion receptors or integrins that bind their specific ligands, which in turn facilitate adhesion to the endothelial cells of blood vessel walls. Platelets form haemostatic plugs with fibrin, a clotting protein derived from fibrinogen.
  • a synthetic platelet thus includes a carrier, such as a cross-linked liposome, that is manufactured to emulate some of the key physical characteristics of platelets (approximate size and shape, and resistance to liposome-cell fusion).
  • the synthetic platelet also includes at least one receptor mimic attached to the carrier (i.e. the outer surface of the liposome).
  • the receptor mimic includes a peptide that mimics a shape and size of a binding site of a natural receptor on a natural platelet.
  • the cross-linked liposome (or other equivalent carrier) includes a plurality of peptides attached to its outer surface, each one functioning as a receptor mimic to thus provide a “multivalent” synthetic platelet with multiple binding sites.
  • each of the peptides is a mimotope that mimics a natural adhesion receptor or integrin found on a natural platelet.
  • a peptide-based material comprising D-amino acids can be used to bind into an integrin receptor to thus inhibit its ligand-binding function.
  • D-peptides (levorotatory peptides) are known in the art, D-peptides (dextrorotary peptides) are preferred because they resist proteolytic degradation.
  • a peptide-based material can be attached to a large carrier (e.g. a liposome, vesicle or other body) at a low coupling ratio for binding to the receptor, thus mimicking a ligand and thus providing a specific, quasi-monovalent inhibition function.
  • a large carrier e.g. a liposome, vesicle or other body
  • the peptide attached to the carrier can be levorotary (L) or dextrorotary (D). Attachment to the large carrier would resist excretion through the kidneys.
  • the carrier preferably a PEG, polyglycidol, or cross-linked liposome
  • the carrier preferably a PEG, polyglycidol, or cross-linked liposome
  • a peptide-based material in accordance with one of the foregoing embodiments would have great utility in the context of an artificial platelet substitute or as an antithrombotic drug.
  • a peptide-based antithrombotic drug would resist proteolytic degradation (proteolysis) because it is made of D-amino acids which form peptide bonds that natural enzymes cannot break down. Furthermore, a peptide drug where the peptide is attached to a large carrier structure would resist excretion through the kidneys.
  • the peptide mimotopes could be attached to a liposome or other (synthetic) platelet-like structure to form an artificial platelet capable of binding to other platelets, either real (natural) platelets or other artificial (synthetic platelets).
  • the peptide mimotopes could be coupled to a carrier at low density (e.g. a quasi-monovalent interaction) to enable these peptides to function as platelet-inhibitors, thus giving rise to a new class of antithrombotic drugs.
  • vWf The von Willebrand factor (vWf) amino acid sequence and available literature were used to select the potential vWf binding site for the integrin, glycoprotein Ib (GPIb).
  • GPIb glycoprotein Ib
  • vWf is a large multimeric blood glycoprotein present in blood plasma that plays a significant role in platelet thrombus formation.
  • the vWf is produced in the Weibel-Palade bodies of the endothelium, in megakaryocytes (stored in a-granules of platelets), and in subendothethial connective tissue.
  • the primary function of von Willebrand factor is binding to other proteins, such as Factor VIII, binding to collagen, binding to platelet GPIb, and binding to other platelet receptors when activated, e.g. by thrombin.
  • the vWf amino acid sequence was used to generate 10-mer L-amino acid overlapping peptides, shifted by two (2), according to the following pattern:
  • peptides were synthesized and remained attached on the cellulose membrane.
  • the membranes were probed by purified GPIb which was detected by anti-GPIb coupled to horseradish peroxidase (HRP). A number of positive spots were found whose sequences were derived from their positions on the membrane.
  • HRP horseradish peroxidase
  • sequences were analyzed in silico by (a) finding their positions in a 3D model of the parent protein (see FIG. 4 ) and then (b) relating that position to the potential vWf-GPIb interactive site. This suggested that the peptides colored black and brown (identified in FIG. 4 as “+ve peptides”) were in the interactive region and thus, as free peptides, could serve as competitive inhibitors of the interaction.
  • FIG. 5 shows the membranes from which four positive sequences were derived.
  • FIG. 6 shows the confirmatory structural results of this analysis for one of the three functional peptides identified.
  • peptides can act as receptors/binding partners, not just as inhibitors, real-time binding was demonstrated by surface plasmon resonance in a Biacore machine.
  • peptides known to interfere with fibrinogen-GPIIbIIIa interaction were synthesized, and coupled to the end of a long (3400 MW) PEG molecule whose other end was attached to biotin, as illustrated schematically in FIG. 7 .
  • fibrinogen is a soluble protein in the blood plasma essential for clotting of blood which the enzyme thrombin converts into the insoluble protein fibrin.
  • the biotin molecule was used to tether down the peptide-PEG onto a streptavidin-modified Biacore chip. This allowed the GPIIbIIa mimicking peptide to be hanging off the free end of the PEG.
  • the binding kinetics i.e., the “on/off rate” between fibrinogen and the peptides were measured. Then, the fibrinogen was released from the peptide. Using several fibrinogen concentrations, it was possible to measure the KD of the binding interaction between the peptide and the fibrinogen.
  • the Langmuir binding analysis is shown in FIG. 8 .
  • a synthetic receptor bestows a number of significant advantages.
  • the receptor since the receptor is synthetic, it does not have to be extracted, or made out of living material, purified, cleaned, etc.
  • it can be made (designed) to carry out any receptor function as long as the three dimensional shape of the receptor is mimicked.
  • the future production of synthetic cells (or cell-replacing materials) would require synthetic receptor functionality and thus a synthetic receptor would be a very significant first step in creating synthetic cells or synthetic platelets.
  • a synthetic receptor can be used on a platelet substitute (i.e. a synthetic or artificial platelet). Furthermore, the synthetic receptor can be used to offer a specific binding capacity for isolating and analyzing ligand molecules without the need for monoclonal antibodies. These synthetic receptors could thus replace monoclonal antibodies in assay systems currently relying on monoclonal antibody technology. This would thus potentially eliminate the need for culturing and maintaining specific antibody-producing clones.
  • the synthetic receptors can be tailored to obtain defined kinetics and binding affinities.
  • the synthetic receptors could also be made from D-amino acids, thereby preventing proteolysis.
US11/484,364 2006-07-11 2006-07-11 Mimotope receptors and inhibitors for platelet-platelet and platelet-endothelium interactions Abandoned US20080015145A1 (en)

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Application Number Priority Date Filing Date Title
US11/484,364 US20080015145A1 (en) 2006-07-11 2006-07-11 Mimotope receptors and inhibitors for platelet-platelet and platelet-endothelium interactions
PCT/CA2006/001699 WO2008006189A1 (en) 2006-07-11 2006-10-17 Mimotope receptors and inhibitors for platelet- platelet and platelet-endothelium interactions
EP12154918A EP2471812A1 (en) 2006-07-11 2006-10-17 Mimotope receptors and inhibitors for platelet-platelet and platelet-endothelium interactions
EP06790853A EP2046827A4 (en) 2006-07-11 2006-10-17 MIMOTOPE RECEPTORS AND INHIBITORS FOR PLATELET AND PLATELET-ENDOTHELIUM INTERACTIONS
CA002657310A CA2657310A1 (en) 2006-07-11 2006-10-17 Mimotope receptors and inhibitors for platelet-platelet and platelet-endothelium interactions
US12/546,811 US7919465B2 (en) 2006-07-11 2009-08-25 Peptide mimotopes that inhibits interaction between a platelet receptor and a platelet receptor ligand

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CN112121231A (zh) * 2020-09-18 2020-12-25 太阳雨林（厦门）生物医药有限公司 一种人工血小板

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