WO1995019568A1 - Hydrophilic signal oligopeptides and methods of therapeutic use - Google Patents

Hydrophilic signal oligopeptides and methods of therapeutic use Download PDF

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WO1995019568A1
WO1995019568A1 PCT/US1995/000575 US9500575W WO9519568A1 WO 1995019568 A1 WO1995019568 A1 WO 1995019568A1 US 9500575 W US9500575 W US 9500575W WO 9519568 A1 WO9519568 A1 WO 9519568A1
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sequence
amino acid
topology
linear
information
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PCT/US1995/000575
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French (fr)
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Matthias Rath
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Matthias Rath
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Priority to AU16810/95A priority Critical patent/AU1681095A/en
Priority to DK95908522T priority patent/DK0744027T3/en
Priority to EP95908522A priority patent/EP0744027B1/en
Priority to AT95908522T priority patent/ATE291230T1/en
Priority to DE69534077T priority patent/DE69534077T2/en
Publication of WO1995019568A1 publication Critical patent/WO1995019568A1/en
Priority to US10/930,300 priority patent/US7300918B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids

Definitions

  • the protein code consists of letters words and sentences .
  • the new discovery are the protein words or verbs. These protein verbs are represented by signal oligopeptides which are localized on the surface of the protein and are represented by the hydrophylicity maxima of the protein. These signal oligopeptides are enriched in charged amino acids in a versatile arrangement with neutral spacer amino acids. The specific signal character of these oligopeptides is determined by a characteristic combination of conformation and charge within the same signal sequence.
  • the discovery of the protein code provides the rationale for deciphering the communication code of diseases Infectious diseases, cancer, cardiovascular and other diseases develop by means of one or more pathogenicity-mediating proteins. Blocking the signal oligopeptides of these proteins allows the specific therapeutic interception of a pathological communication and thereby blocks disease propagation.
  • Synthetic analogs to signal oligopeptides can be used therapeutically in several ways.
  • synthetic analogues to signal oligopeptides can be used as competitive inhibitors of pathological communication.
  • synthetic analogs to signal oligopeptides can be used as vaccines. This second therapeutic approach makes use of the fact that signal oligopeptides on the surface of the protein are identical with the antigenicity determining epitopes of this protein. Thus, antibodies are interceptors of metabolic communication. By binding to the signal oligopeptide of a protein antibodies and other mediators of immune response reduce or block its metabolic interaction. If synthetic analogs to signal oligopeptides are used as vaccines it is necessary to render these peptides antigenic and to allow their discrimination as 'non-self'. Synthetic analogs to signal oligopeptides can be rendered immunogenic by coupling them to haptens and by other conventional methods.
  • This patent also claims new methods by which oligopeptide sequences can be rendered immunogenic.
  • This new method is based on the discovery of the primary structural principles determining immunogenicity. The discrimination between self and non-self between species and between individuals is primarily based on amino acid residue substitutions or other residue variations within the signal oligopeptide sequences of a protein. By making use of this discovery effective therapeutic signal oligopeptides can be rapidly produced in the following way signal oligopeptides of a given protein in one species are the antigenicity determinants of this protein in another species.
  • the synthetic signal oligopeptide vaccines are designed by copying corresponding amino acid signal sequences from another species
  • a glucagon signal oligopeptide vaccine for the treatment of diabetic patients would be based on glucagon signal sequences from rabbits sheep mice or other species.
  • a titration of the therapeutic efficiency is possible : The greater the genetic and evolutionary distance of the selected species to humans the greater its antigenicity and consequently the greater its therapeutic efficiency as a vaccine.
  • FIG. 1 This figure illustrates several of the protein code principles.
  • Legibility Within the amino acid sequence of a protein one or more oligopeptides represent the words - or verbs - of the protein code which mediates its action and interaction
  • Accessibility The signal sequences of a protein are enriched in charged amino acids and represent the hydrophylicity maxima within the potential sequence ( Figure 1 A).
  • Variability An infinite number of possible combinations between amino acids with different charges as well as neutral residues provide the variability for differentiated metabolic communication.
  • Specificity The specificity of a signal sequence is the result of a characteristic combination of charge distribution and structural conformation within the signal oligopeptide sequence. Oppositely charged amino acids can attract each other thereby enhancing confirmational specificity.
  • Signal oligopeptides mediate specific information transfer to their metabolic counterparts ( Figure 1 B). Differentiation: Substitution, deletion or other amino acid residue variations within the signal sequence of a protein enable differentiation between 'self' and 'non-self'. Signal sequences are the antigenic epitopes of a protein and are responsible for potential immune responses when exposed to other organisms. Interception Direct and indirect Peptide Interception Therapy (PIT) can be used to intercept undesired or pathological communication and thereby block the disease. In direct PIT synthetic analogs to signal oligopeptides can be used to competitively inhibit the interaction of proteins ( Figure 1C). Indirect PIT makes use of synthetic oligopeptides rendered immunogenic. These vaccines stimulating the production of antibodies which block pathological communication pathways not only in the prevention and treatment of infectious diseases but also in the therapy of neoplastic diseases, metabolic disorders and other diseases ( Figure 1D).
  • PIT Interception Direct and indirect Peptide Interception Therapy
  • FIG. 1 Fundamentals of Peptide Interception Therapy (PIT) Proteins are essential earners of specific metabolic information; moreover, proteins are frequently mobile which makes them ideal and versatile communication molecules. This figure illustrates several key elements of PIT PIT is an interception therapy. To promote protein action, the entire three dimensional protein structure (protein sentence) is required. To intercept protein action, only the signal oligopeptide (verb) has to be blocked by direct or indirect PIT.
  • PIT Peptide Interception Therapy
  • Figure 2 shows the principles of Direct Peptide Interception Therapy (Direct PIT) including the methods for identification, design, development and therapeutic use of synthetic analogs to signal oligopeptides in Peptide Interception Therapy as direct competitive inhibitors of selected protein actions.
  • Direct PIT Direct Peptide Interception Therapy
  • FIG. 3 This figure shows the principles of Indirect Peptide Interception Therapy (Indirect PIT) including the methods for identification, design, development and therapeutic use of synthetic analogs to signal oligopeptides in Peptide Interception Therapy as vaccines to stimulate a specific immune response with the aim to decrease or block selected protein actions.
  • Indirect PIT Indirect Peptide Interception Therapy
  • FIG 4. This figure shows the principles of Peptide Regulation Therapy (PRT) including the methods for identification, design, development and therapeutic use ot synthetic analogs to signal oligopeptides in Peptide Regulation Therapy as negative feed-back regulators for the synthesis rate of selected proteins.
  • PRT Peptide Regulation Therapy
  • Figure 5. Amino acid sequence selection and therapeutic design of peptide vaccines for Indirect Peptide Interception Therapy, exemplified for the development of glucagon vaccines in clinical therapy of diabetes mellitus.
  • FIG. 6 Peptide therapy in diabetes. This figure shows the potential signal sequences of proglucagon and therapeutic alternatives for peptide therapy in diabetic patients. Conventional treatment in diabetes focuses on an increased availability of insulin Peptide therapy enables an alternative approach . Synthetic analogs to the signal sequences of glucagon can be therapeutically used to attenuate the effect of this insulin antagonist Note the three hydrophilicity peaks in the glucagon precursor sequence (A,B,C).
  • the mature glucagon hormone is activated by contact and charge redistribution within the peaks A and C PIT therapy could have two distinct targets: Blocking charge redistribution of precursor molecule (PIT for Peak A or C) prevents activation of precursor to mature hormone PIT targeting peak B prevents the action of the glucagon hormone Vaccination with synthetic glucagon signal oligopeptides rendered immunogenic could become a baseline treatment for diabetic patients.
  • FIG. 7 Peptide therapy in HIV infections. Synthetic analogs to signal oligopeptides of the HIV envelope protein GP 160 or the cell receptor CD4 can be used as vaccines. The specific antibodies produced should effectively inhibit the infection of cells. The hydrophylicity blot revealing potential signal sequences of GP 160 is shown in the upper part of the figure. Other targets of HIV peptide therapy are the regulator proteins Rev and Tat with the aim to block viral replication.
  • the protein code is determined by the following principles:
  • the protein code is universally valid Proteins are important earners of metabolic information in living organisms.
  • the protein code is the biological language for protein-mediated information transfer during health and disease.
  • the protein code is the underlying communication principle for the interaction of antigens with antibodies, enzymes with substrates receptors with ligands, adhesion molecules with integrins and other forms of protein communication.
  • the protein code is compatible with other elements of biological communication
  • the protein code and the genetic code are closely connected.
  • the genetic code determines the structure of proteins and, thereby their function.
  • the protein code determines the relation between structure and function within a protein sequence and, thereby, the specific biological action. Specific and efficient action of a protein are responsible for the advantage of a gene and, therefore, for the survival of the genetic information encoding for the protein.
  • the protein code is composed of letters, sentences and words.
  • the protein code fetters are represented by the amino acid residues of a protein.
  • the protein code sentence is represented by the complete three dimensional structure of the protein which ultimately determines its action.
  • the decisive signal of protein communication is mediated by the protein code words.
  • These protein code words are represented by one or more signal oligopeptides within a protein sequence.
  • verbs are the action words within a sentence.
  • Signal oligopeptides are the verbs of the protein code and determine the action of the protein Interference with these signal oligopeptides can lead to substantial modification or loss of the biological message of a protein.
  • the protein code has to be accessible Protein information transfer and protein interaction is dependent on the accessibility of the signal sequence.
  • Signal oligopeptides are generally represented by the regions of maximum hydrophilicity on the surface of the protein molecule. Critical determinants for these hydrophilicity maxima is an enrichment of the cationic amino acid residues arginine and lysine and/or the aniomc amino acid residues glutamate and aspartate.
  • the protein code requires a sufficient reservoir of structural variations encoding for a large number of diverse signals.
  • the protein code is based on optimum variability.
  • the protein code is based on an almost infinite number of possible signal oligopeptide structures.
  • a specific arrangement of charged amino acid residues in combination with a variable number of uncharged residues within signal tripeptides tetrapeptides, pentapeptides, hexapetides or larger polypeptides provide the necessary number of possible residue combinations for a giant signal reservoir.
  • a new type of signals is represented by oligopeptides which obtain their characteristic conformation by a specific arrangement of oppositely charged amino acid residues within this oligopeptide sequence. These residues with opposite charge can attract each other thereby modulating a characteristic folding of this signal sequence
  • the cationic residue arginine and the anionic residue aspartate attract each other leading to a characteristic folding of this tripeptide around the 'spacer' residue glycine.
  • the protein code is specific. The specific and reliable metabolic function of a protein is dependent on the specificity of its biological signal sequences.
  • the signal character of a specific oligopeptide is determined by a characteristic combination of electrical charge with structural conformation. Within a protein RGD and analogous tripeptides can serve as strong primary anchors while the specific biological message is mediated by additional longer and more complex signal oligopeptides.
  • the protein code provides the basis for the immunological differentiation between individuals and species. Substitutions, omissions, and other variations of one or more amino acid residues within the signal sequence of the protein enable an organism to differentiate between 'self' and 'non-self'.
  • the protein code comprises the basic language of immunology.
  • the protein code is a key for individual development within a species as well as for the evolutionary diversification of species.
  • the effectiveness of signal oligopeptides to mediate specific biological messages were the ultimate criterion for the evolutionary advantage of a protein and, thus, for the evolutionary survival of the gene encoding for it.
  • Genetic mutations leading to the substitution of one or more amino acid residues within a signal oligopeptide sequence were an economic and therefore frequent mechanism to modulate and differentiate protein action and thereby promoting evolutionary diversification.
  • the protein code is interceptable.
  • the signal oligopeptides of a protein are identical with the potential antigenic determinants.
  • Antibodies and other mediators of immune response are interceptors of specific biological communication.
  • Signal oligopeptides as promoters of differentiated protein communication and immune response mediators as interceptors can form a sophisticated network of biological communication. Decoding the physiologic aspects of this communication network will lead to a precise understanding of millions of metabolic interactions including the principles for development and differentiation of the body. Decoding the pathophysiological aspects of this communication network will lead to the therapeutic control of many diseases and eventually to their eradication as causes of human mortality.
  • the protein code could also provide a missing link in the regulation of protein synthesis.
  • the signal sequences of a protein may have important feed-back functions directly or indirectly modulating the synthesis rate of this protein.
  • Peptide Interception Therapy is defined as the specific therapeutic interception of pathological or undesired protein actions and interactions by the therapeutic use of synthetic analogs to the signal oligopeptide sequences of this protein.
  • Peptide Regulation Therapy makes therapeutic use of synthetic analogs to signal oligopeptide sequences to decrease the synthesis rate of an undesired protein via feed-back mechanisms.
  • Peptide Interception Therapy uses the discovery of the protein code: To promote protein action the entire three dimensional protein structure (protein sentence) is required . To intercept protein action, only the signal oligopeptide (protein verb) has to be therapeutically blocked.
  • signal oligopeptide sequences are located on the surface of the protein and are epresented by the hydrophilicity maxima within the ammo acid sequence of the protein.
  • the signal oligopeptide sequences of a protein can be identified from its primary structure by use of a protein data base in combination with a suitable algorithm, such as for hydrophilicity or surface probability In this algorithm the highest hydrophilicity or probability values have to be assigned to the charged amino acids lysine, arginine, aspartate and glutamate followed by asparagine and glutamine.
  • Synthetic analogs to signal oligopeptide sequences can be therapeutically used.
  • An unlimited number of signal oligopeptide analogs can be synthesized covering the entire sequence of a selected hydrophylicity peak or parts of it.
  • Signal tetrapeptides, pentapeptides, hexapeptides and longer peptides represent primary candidates for specific peptide therapy. Shorter peptides, such as the tripeptide RGD, are less specific and ubiquitous side effects limit their broad therapeutic use.
  • PIT Peptide Interception Therapy
  • Direct PIT uses synthetic analogs to signal oligopeptides as competitive inhibitors of pathological or undesired metabolic interaction.
  • Indirect PIT uses these synthetic analogs as vaccines to stimulate the production of specific antibodies.
  • indirect PIT the antibodies, not the therapeutic peptide itself, function as interceptors of protein communication.
  • Direct Peptide Interception Therapy uses synthetic analogs to signal oligopeptides as direct competitive inhibitors for undesired protein communication. Direct blocking of pathogenicity mediating protein communication leads to the control of the related disease or clinical condition. This therapeutic approach would be preferentially used in acute conditions, e g antithrombotic or fibrinolytic therapy. Direct PIT would be preferentially used intravenously in higher therapeutic dosages of the synthetic peptide. Poly-oligopeptide analogs time release delivery systems and other modifications of the peptide delivery mechanism can be used to extend the range of possible therapeutic applications.
  • Indirect Peptide Interception Therapy (Indirect PIT).
  • Today vaccines are essentially limited to prophylaxis and therapy of infectious diseases Indirect PIT enables the extension of the preventive and therapeutic use of vaccines to all areas of medicine.
  • the great advantage of oligopeptide vaccines compared to conventional vaccines is that not the entire protein is used as a vaccine but only synthetic analogs to one or more of the signal oligopeptides of the selected protein.
  • Indirect PIT is based on the therapeutic use of antibodies produced by the patient s own immune system against the signal sequences of proteins mediating pathogenicity for undesired metabolic action. Indirect PIT is preferentially used for preventive therapy for the treatment of chronic conditions or as adjuncts to direct PIT or other forms of acute therapy. 10. Indirect PIT makes use of two newly discovered principles of immunology: First, the signal oligopeptides of a given protein are identical with its potential antigenicity determining regions (antigenic epitopes). Second, the primary mechanism determining antigenicity between different individuals and different species are amino acid residue substitutions, omissions and other residue variations within the signal oligopeptide sequence(s) of a protein.
  • Therapeutic peptide design for indirect PIT is based on the following principle: Signal oligopeptides of a given protein in one species are the antigenic epitopes of this protein for the immune system of another species. To block the action of a pathogenicity-mediating protein in the treatment of a human disease, the amino acid residue sequence of the oligopeptide vaccines should be homologous to the signal sequences of the same protein - but from another species.
  • a glucagon signal oligopeptide vaccine for the treatment of diabetic patients would be based on the glucagon signal sequences from rabbits, sheep, mice or other species. The aim of this residue manipulation is to create an antigenic epitope without compromising the ability of the antibodies produced to effectively block the metabolic interaction of the protein. This therapeutic approach mimics nature's way to discriminate between 'self' and 'non-self' and make therapeutic use of it.
  • the designer of therapeutic compounds for indirect PIT can also make use of the evolutionary clock. The further apart two species are in evolution, the more amino acid residue mutations occurred, including mutations in the signal oligopeptide sequences, and the more antigenic is the therapeutic peptide composed of this sequence. A titration of the therapeutic efficiency of indirect PIT is possible: Indirect PIT therapy with synthetic analogs to glucagon signal oligopeptides from a fish species are more effective than those from a mammalian species in blocking human glucagon action.
  • Antigenicity required for effective indirect PIT therapy can also be stimulated in conventional ways, e.g. by coupling the therapeutic peptides to defined haptens or other immunogenic compounds enhancing 'non-self' recognition.
  • a third therapeutic mechanism using synthetic analogs to signal oligopeptides is as feed-back regulators for protein synthesis.
  • This form of therapy is designated Peptide Regulation Therapy (PRT).
  • PRT Peptide Regulation Therapy
  • the synthesis rate of many proteins is determined by the amount of protein end-product available.
  • the signal sequences of pathogenicity mediating proteins can be used to decrease the synthesis of this protein via direct or indirect feed-back mechanisms.
  • oligopeptide antigen Optimum length of oligopeptide antigen. To optimize specificity of the antigen the signal oligopeptide should be at least a tetrapeptide or preferentially longer oligopeptides.
  • Peptide therapy enables maximum therapeutic specificity. Based on the precise understanding of the structure/function relation of specific protein signals, peptide therapy allows therapeutic targeting with unprecedented specificity.
  • peptide therapy compared to conventional therapies.
  • the advantages of peptide therapy become even more obvious when this novel therapeutic approach is compared to conventional therapies or alternative future therapies.
  • Conventional drug therapy is frequently compromised by an unknown therapeutic mechanism and by a wide range of side effects and considerable toxicity.
  • Gene therapy is compromised by limited availability, its technological requirements and its high costs which restncts its therapeutic application to exclusive areas in the foreseeable future Heterologous or synthetic antibody therapy, the therapeutic application of antibodies produced outside of the patient's body, can cause incalculable adverse reactions by the patient's immune system against these 'foreign' antibodies.
  • peptide therapy makes elegant use of the patient's own immune system thereby excluding adverse immunological reactions.
  • Infectious diseases The most immediate application of peptide therapy is the prevention and treatment of infectious diseases. Every stage of any type of infectious disease is controlled by proteins which mediate adhesion, invasion and other mechanisms of pathogenicity Effective therapeutic interception of biological signals within these pathogenicity-mediating proteins must lead to the control of the infection itself. Table I lists some of the most frequent infectious diseases and potential target proteins for peptide therapy. As discussed above, therapeutic peptides can be applied in acute treatment of infectious diseases and as vaccines.
  • Neoplastic Diseases Another area with immediate applications for peptide therapy is the treatment of neoplastic diseases Invasive growth and metastatic spread of any type of cancer is mediated by certain proteins and their signal sequences. Synthetic analogs to the signal sequences of these proteins should be developed as an effective therapy for different forms of cancer in their early stage as well as their invasive and metastatic stages.
  • Metabolic disorders A novel therapeutic area for peptide therapy is the treatment of metabolic disorders.
  • the potential of peptide therapy is exemplified here for the treatment of diabetes and hypertension.
  • renin angiotensin system and particularly the angiotensin-converting enzyme (ACE) are a continuous focus of antihypertensive drug development. Renin, angiotensin I and II as well as ACE are also promising targets for peptide therapy. Therapeutic use of synthetic analogs to the signal sequences of any of these proteins will lead to decreased blood pressure. Since in most cases hypertension is a chronic condition the therapeutic use of renin, angiotensin or ACE signal peptide vaccines should be considered.
  • ACE angiotensin-converting enzyme
  • HERPES VIRUS 1 (HSV1) GLYCOPROTEIN B INFORMATION FOR SEQUENCE ID NO 239

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Abstract

The instant invention is directed to a method of identifying signal oligopeptides through the use of algorithms, the use of signal oligopeptides as vaccines and as immunogens to produce antibodies.

Description

HYDROPHILIC SIGNAL OLIGOPEPTIDES AND METHODS OF THERAPEUTIC USE
Field of Invention
This patent is a continuation in part patent to serial number 07/997,727 and 08/045,394 which introduced new oligopeptide sequences based on the discovery of the protein code. The present patent claims further specific signal oligopeptides, further specifications of the methods of their identification, their therapeutic use as well as their application for diagnostic purposes.
References
1 Watson JD, Crick FHC.1953. Nature 171:737
2 Rath, M. 1993 J. Orthom. Medicine 8:11
3 Rath, M.1994 J Appl. Nutr. (in Press)
Background
This patent summarizes the discovery of the protein code and claims the therapeutic and diagnostic use of this new biological language for different areas of medicine .
The discovery of the genetic code four decades ago defined the principles by which genes encode for proteins (1). The protein code, however, the biological language by which proteins act and interact has remained obscure. Now the protein code is discovered (2,3). The interaction of hormones and other ligands with their respective receptors, of enzymes with protein substrates, of adhesive proteins with integrins, and of antibodies with antigens as well as other protein actions and interactions are determined by the same structure/function principles and the same biological language. For a very limited number of proteins the hydrophobic interior of the protein forms the active center which also determines their function In the vast majority of proteins, however, biological activity is primarily mediated via specific surface structures which mediate their specific functions. The structure/function principles determining these protein actions are discovered (1) and they are hereafter referred to as the protein code.
Summary of the Invention
Like the human language the protein code consists of letters words and sentences . The letters (amino acids) and sentences (complete three dimensional protein) had been known before. The new discovery are the protein words or verbs. These protein verbs are represented by signal oligopeptides which are localized on the surface of the protein and are represented by the hydrophylicity maxima of the protein. These signal oligopeptides are enriched in charged amino acids in a versatile arrangement with neutral spacer amino acids. The specific signal character of these oligopeptides is determined by a characteristic combination of conformation and charge within the same signal sequence.
Like in the human language the whole sentence (complete three dimensional protein is needed to determine the specific and complete action of any given protein In the human language eliminating or changing the verb of a sentence renders the whole sentence meaningless. Similarly, blocking the protein code verbs (signal oligopeptides) can be therapeutically used to block the undesired action or interaction of an entire protein.
The discovery of the protein code provides the rationale for deciphering the communication code of diseases Infectious diseases, cancer, cardiovascular and other diseases develop by means of one or more pathogenicity-mediating proteins. Blocking the signal oligopeptides of these proteins allows the specific therapeutic interception of a pathological communication and thereby blocks disease propagation.
Synthetic analogs to signal oligopeptides can be used therapeutically in several ways. First, synthetic analogues to signal oligopeptides can be used as competitive inhibitors of pathological communication. Second, synthetic analogs to signal oligopeptides can be used as vaccines. This second therapeutic approach makes use of the fact that signal oligopeptides on the surface of the protein are identical with the antigenicity determining epitopes of this protein. Thus, antibodies are interceptors of metabolic communication. By binding to the signal oligopeptide of a protein antibodies and other mediators of immune response reduce or block its metabolic interaction. If synthetic analogs to signal oligopeptides are used as vaccines it is necessary to render these peptides antigenic and to allow their discrimination as 'non-self'. Synthetic analogs to signal oligopeptides can be rendered immunogenic by coupling them to haptens and by other conventional methods.
This patent also claims new methods by which oligopeptide sequences can be rendered immunogenic. This new method is based on the discovery of the primary structural principles determining immunogenicity. The discrimination between self and non-self between species and between individuals is primarily based on amino acid residue substitutions or other residue variations within the signal oligopeptide sequences of a protein. By making use of this discovery effective therapeutic signal oligopeptides can be rapidly produced in the following way signal oligopeptides of a given protein in one species are the antigenicity determinants of this protein in another species. To block the action of a pathogenicity-mediating protein in the treatment of a human disease the synthetic signal oligopeptide vaccines are designed by copying corresponding amino acid signal sequences from another species A glucagon signal oligopeptide vaccine for the treatment of diabetic patients would be based on glucagon signal sequences from rabbits sheep mice or other species. A titration of the therapeutic efficiency is possible : The greater the genetic and evolutionary distance of the selected species to humans the greater its antigenicity and consequently the greater its therapeutic efficiency as a vaccine.
This patent also includes claims for the use of new algorithms to identify signal oligopeptides. Moreover claims are made to use the technology presented in this patent for the development of specific antibodies with predefined specificity and characteristics and their in vitro use for diagnostic purposes Detailed Description of the Figures
Figure 1. This figure illustrates several of the protein code principles. Legibility: Within the amino acid sequence of a protein one or more oligopeptides represent the words - or verbs - of the protein code which mediates its action and interaction, Accessibility: The signal sequences of a protein are enriched in charged amino acids and represent the hydrophylicity maxima within the potential sequence (Figure 1 A). Variability: An infinite number of possible combinations between amino acids with different charges as well as neutral residues provide the variability for differentiated metabolic communication. Specificity: The specificity of a signal sequence is the result of a characteristic combination of charge distribution and structural conformation within the signal oligopeptide sequence. Oppositely charged amino acids can attract each other thereby enhancing confirmational specificity. Signal oligopeptides mediate specific information transfer to their metabolic counterparts (Figure 1 B). Differentiation: Substitution, deletion or other amino acid residue variations within the signal sequence of a protein enable differentiation between 'self' and 'non-self'. Signal sequences are the antigenic epitopes of a protein and are responsible for potential immune responses when exposed to other organisms. Interception Direct and indirect Peptide Interception Therapy (PIT) can be used to intercept undesired or pathological communication and thereby block the disease. In direct PIT synthetic analogs to signal oligopeptides can be used to competitively inhibit the interaction of proteins (Figure 1C). Indirect PIT makes use of synthetic oligopeptides rendered immunogenic. These vaccines stimulating the production of antibodies which block pathological communication pathways not only in the prevention and treatment of infectious diseases but also in the therapy of neoplastic diseases, metabolic disorders and other diseases (Figure 1D).
Figure 2. Fundamentals of Peptide Interception Therapy (PIT) Proteins are essential earners of specific metabolic information; moreover, proteins are frequently mobile which makes them ideal and versatile communication molecules. This figure illustrates several key elements of PIT PIT is an interception therapy. To promote protein action, the entire three dimensional protein structure (protein sentence) is required. To intercept protein action, only the signal oligopeptide (verb) has to be blocked by direct or indirect PIT.
Figure 2 shows the principles of Direct Peptide Interception Therapy (Direct PIT) including the methods for identification, design, development and therapeutic use of synthetic analogs to signal oligopeptides in Peptide Interception Therapy as direct competitive inhibitors of selected protein actions.
Figure 3. This figure shows the principles of Indirect Peptide Interception Therapy (Indirect PIT) including the methods for identification, design, development and therapeutic use of synthetic analogs to signal oligopeptides in Peptide Interception Therapy as vaccines to stimulate a specific immune response with the aim to decrease or block selected protein actions.
Figure 4. This figure shows the principles of Peptide Regulation Therapy (PRT) including the methods for identification, design, development and therapeutic use ot synthetic analogs to signal oligopeptides in Peptide Regulation Therapy as negative feed-back regulators for the synthesis rate of selected proteins. Figure 5. Amino acid sequence selection and therapeutic design of peptide vaccines for Indirect Peptide Interception Therapy, exemplified for the development of glucagon vaccines in clinical therapy of diabetes mellitus.
Figure 6. Peptide therapy in diabetes. This figure shows the potential signal sequences of proglucagon and therapeutic alternatives for peptide therapy in diabetic patients. Conventional treatment in diabetes focuses on an increased availability of insulin Peptide therapy enables an alternative approach . Synthetic analogs to the signal sequences of glucagon can be therapeutically used to attenuate the effect of this insulin antagonist Note the three hydrophilicity peaks in the glucagon precursor sequence (A,B,C). The mature glucagon hormone is activated by contact and charge redistribution within the peaks A and C PIT therapy could have two distinct targets: Blocking charge redistribution of precursor molecule (PIT for Peak A or C) prevents activation of precursor to mature hormone PIT targeting peak B prevents the action of the glucagon hormone Vaccination with synthetic glucagon signal oligopeptides rendered immunogenic could become a baseline treatment for diabetic patients.
Figure 7. Peptide therapy in HIV infections. Synthetic analogs to signal oligopeptides of the HIV envelope protein GP 160 or the cell receptor CD4 can be used as vaccines. The specific antibodies produced should effectively inhibit the infection of cells. The hydrophylicity blot revealing potential signal sequences of GP 160 is shown in the upper part of the figure. Other targets of HIV peptide therapy are the regulator proteins Rev and Tat with the aim to block viral replication.
Detailed Description of the Invention
Decisive inventions have been presented in my earlier patent s with the serial numbers 07/997,727 and 08/045,394. This continuation in part patent includes further details and a comprehensive
understanding of the principles of the Protein Code as well as of Peptide Interception Therapy (PIT). They are summarized as follows:
I. Determining Principles of the Protein Code
The protein code is determined by the following principles:
1. Universality. The protein code is universally valid Proteins are important earners of metabolic information in living organisms. The protein code is the biological language for protein-mediated information transfer during health and disease. The protein code is the underlying communication principle for the interaction of antigens with antibodies, enzymes with substrates receptors with ligands, adhesion molecules with integrins and other forms of protein communication.
2. Compatibility. The protein code is compatible with other elements of biological communication The protein code and the genetic code are closely connected. The genetic code determines the structure of proteins and, thereby their function. The protein code determines the relation between structure and function within a protein sequence and, thereby, the specific biological action. Specific and efficient action of a protein are responsible for the advantage of a gene and, therefore, for the survival of the genetic information encoding for the protein.
3. Legibility. The protein code is composed of letters, sentences and words. The protein code fetters are represented by the amino acid residues of a protein. The protein code sentence is represented by the complete three dimensional structure of the protein which ultimately determines its action. The decisive signal of protein communication is mediated by the protein code words. These protein code words are represented by one or more signal oligopeptides within a protein sequence. In the human language verbs are the action words within a sentence. Signal oligopeptides are the verbs of the protein code and determine the action of the protein Interference with these signal oligopeptides can lead to substantial modification or loss of the biological message of a protein.
4. Accessibility. The protein code has to be accessible Protein information transfer and protein interaction is dependent on the accessibility of the signal sequence. Signal oligopeptides are generally represented by the regions of maximum hydrophilicity on the surface of the protein molecule. Critical determinants for these hydrophilicity maxima is an enrichment of the cationic amino acid residues arginine and lysine and/or the aniomc amino acid residues glutamate and aspartate.
5. Variability. The protein code requires a sufficient reservoir of structural variations encoding for a large number of diverse signals. The protein code is based on optimum variability. The protein code is based on an almost infinite number of possible signal oligopeptide structures. A specific arrangement of charged amino acid residues in combination with a variable number of uncharged residues within signal tripeptides tetrapeptides, pentapeptides, hexapetides or larger polypeptides provide the necessary number of possible residue combinations for a giant signal reservoir.
A new type of signals is represented by oligopeptides which obtain their characteristic conformation by a specific arrangement of oppositely charged amino acid residues within this oligopeptide sequence. These residues with opposite charge can attract each other thereby modulating a characteristic folding of this signal sequence In the signal sequence RGD the cationic residue arginine and the anionic residue aspartate attract each other leading to a characteristic folding of this tripeptide around the 'spacer' residue glycine.
6. Specificity. The protein code is specific. The specific and reliable metabolic function of a protein is dependent on the specificity of its biological signal sequences. The signal character of a specific oligopeptide is determined by a characteristic combination of electrical charge with structural conformation. Within a protein RGD and analogous tripeptides can serve as strong primary anchors while the specific biological message is mediated by additional longer and more complex signal oligopeptides.
7 Differentiation. The protein code provides the basis for the immunological differentiation between individuals and species. Substitutions, omissions, and other variations of one or more amino acid residues within the signal sequence of the protein enable an organism to differentiate between 'self' and 'non-self'. Thus, the protein code comprises the basic language of immunology.
8. Diversification. The protein code is a key for individual development within a species as well as for the evolutionary diversification of species. The effectiveness of signal oligopeptides to mediate specific biological messages were the ultimate criterion for the evolutionary advantage of a protein and, thus, for the evolutionary survival of the gene encoding for it. Genetic mutations leading to the substitution of one or more amino acid residues within a signal oligopeptide sequence were an economic and therefore frequent mechanism to modulate and differentiate protein action and thereby promoting evolutionary diversification.
9. Interception. The protein code is interceptable. The signal oligopeptides of a protein are identical with the potential antigenic determinants. Antibodies and other mediators of immune response are interceptors of specific biological communication. Signal oligopeptides as promoters of differentiated protein communication and immune response mediators as interceptors can form a sophisticated network of biological communication. Decoding the physiologic aspects of this communication network will lead to a precise understanding of millions of metabolic interactions including the principles for development and differentiation of the body. Decoding the pathophysiological aspects of this communication network will lead to the therapeutic control of many diseases and eventually to their eradication as causes of human mortality.
10. Regulation. The protein code could also provide a missing link in the regulation of protein synthesis. The signal sequences of a protein may have important feed-back functions directly or indirectly modulating the synthesis rate of this protein.
II. Principles of Peptide Interception Therapy (PIT) and of Peptide Regulation Therapy ( PRT)
1. The metabolic interaction of proteins is primarily modulated by one or more oligopeptide signal sequences which determine the metabolic interaction of this protein Peptide Interception Therapy (PIT) is defined as the specific therapeutic interception of pathological or undesired protein actions and interactions by the therapeutic use of synthetic analogs to the signal oligopeptide sequences of this protein. Peptide Regulation Therapy (PRT) makes therapeutic use of synthetic analogs to signal oligopeptide sequences to decrease the synthesis rate of an undesired protein via feed-back mechanisms.
2 Peptide Interception Therapy uses the discovery of the protein code: To promote protein action the entire three dimensional protein structure (protein sentence) is required . To intercept protein action, only the signal oligopeptide (protein verb) has to be therapeutically blocked.
3. These signal oligopeptide sequences are located on the surface of the protein and are epresented by the hydrophilicity maxima within the ammo acid sequence of the protein. The signal oligopeptide sequences of a protein can be identified from its primary structure by use of a protein data base in combination with a suitable algorithm, such as for hydrophilicity or surface probability In this algorithm the highest hydrophilicity or probability values have to be assigned to the charged amino acids lysine, arginine, aspartate and glutamate followed by asparagine and glutamine.
4. Synthetic analogs to signal oligopeptide sequences can be therapeutically used. An unlimited number of signal oligopeptide analogs can be synthesized covering the entire sequence of a selected hydrophylicity peak or parts of it.
5. Signal tetrapeptides, pentapeptides, hexapeptides and longer peptides represent primary candidates for specific peptide therapy. Shorter peptides, such as the tripeptide RGD, are less specific and ubiquitous side effects limit their broad therapeutic use.
6 Peptide Interception Therapy (PIT) can be used in two principal ways: Direct PIT uses synthetic analogs to signal oligopeptides as competitive inhibitors of pathological or undesired metabolic interaction. Indirect PIT uses these synthetic analogs as vaccines to stimulate the production of specific antibodies. In indirect PIT the antibodies, not the therapeutic peptide itself, function as interceptors of protein communication.
7. Direct Peptide Interception Therapy (Direct PIT) uses synthetic analogs to signal oligopeptides as direct competitive inhibitors for undesired protein communication. Direct blocking of pathogenicity mediating protein communication leads to the control of the related disease or clinical condition. This therapeutic approach would be preferentially used in acute conditions, e g antithrombotic or fibrinolytic therapy. Direct PIT would be preferentially used intravenously in higher therapeutic dosages of the synthetic peptide. Poly-oligopeptide analogs time release delivery systems and other modifications of the peptide delivery mechanism can be used to extend the range of possible therapeutic applications.
8. Indirect Peptide Interception Therapy (Indirect PIT). Today vaccines are essentially limited to prophylaxis and therapy of infectious diseases Indirect PIT enables the extension of the preventive and therapeutic use of vaccines to all areas of medicine. The great advantage of oligopeptide vaccines compared to conventional vaccines is that not the entire protein is used as a vaccine but only synthetic analogs to one or more of the signal oligopeptides of the selected protein.
9 Indirect PIT is based on the therapeutic use of antibodies produced by the patient s own immune system against the signal sequences of proteins mediating pathogenicity for undesired metabolic action. Indirect PIT is preferentially used for preventive therapy for the treatment of chronic conditions or as adjuncts to direct PIT or other forms of acute therapy. 10. Indirect PIT makes use of two newly discovered principles of immunology: First, the signal oligopeptides of a given protein are identical with its potential antigenicity determining regions (antigenic epitopes). Second, the primary mechanism determining antigenicity between different individuals and different species are amino acid residue substitutions, omissions and other residue variations within the signal oligopeptide sequence(s) of a protein.
11. Therapeutic peptide design for indirect PIT is based on the following principle: Signal oligopeptides of a given protein in one species are the antigenic epitopes of this protein for the immune system of another species. To block the action of a pathogenicity-mediating protein in the treatment of a human disease, the amino acid residue sequence of the oligopeptide vaccines should be homologous to the signal sequences of the same protein - but from another species. A glucagon signal oligopeptide vaccine for the treatment of diabetic patients would be based on the glucagon signal sequences from rabbits, sheep, mice or other species. The aim of this residue manipulation is to create an antigenic epitope without compromising the ability of the antibodies produced to effectively block the metabolic interaction of the protein. This therapeutic approach mimics nature's way to discriminate between 'self' and 'non-self' and make therapeutic use of it.
12. The designer of therapeutic compounds for indirect PIT can also make use of the evolutionary clock. The further apart two species are in evolution, the more amino acid residue mutations occurred, including mutations in the signal oligopeptide sequences, and the more antigenic is the therapeutic peptide composed of this sequence. A titration of the therapeutic efficiency of indirect PIT is possible: Indirect PIT therapy with synthetic analogs to glucagon signal oligopeptides from a fish species are more effective than those from a mammalian species in blocking human glucagon action.
13. Antigenicity required for effective indirect PIT therapy can also be stimulated in conventional ways, e.g. by coupling the therapeutic peptides to defined haptens or other immunogenic compounds enhancing 'non-self' recognition.
14. A third therapeutic mechanism using synthetic analogs to signal oligopeptides is as feed-back regulators for protein synthesis. This form of therapy is designated Peptide Regulation Therapy (PRT). The synthesis rate of many proteins is determined by the amount of protein end-product available. The signal sequences of pathogenicity mediating proteins can be used to decrease the synthesis of this protein via direct or indirect feed-back mechanisms.
III. Use of Signal Oligopeptides for Development of In vitro Diagnostics
This patent also covers claims to use the technology presented for the production of in vitro antibodies for diagnostic purposes. In the future polyclonal or monoclonal antibodies for a protein can be manufactured in the following way:
1. Identification of antigen. Synthetic analogs to one or more signal sequences of a proteins are used as antigens. These signal sequences are determined from a data base by making use of algorithms for hydrophylicity or surface probability. For clinical diagnostics the signal sequence of the protein should preferentially be chosen from a database of human proteins.
2. Optimum length of oligopeptide antigen. To optimize specificity of the antigen the signal oligopeptide should be at least a tetrapeptide or preferentially longer oligopeptides.
3. Production of antigen. Polyclonal or monoclonal antibodies are raised according to established methods using adjuvants or other haptens.
4. Testing of antibody specificity. The same synthetic signal oligopeptides used as antigens can be used to test the specificity of the antibodies.
IV. Advantages of Peptide Therapy
1. Efficacy. Peptide therapy is a highly effective form of treatment. The discovery of the peptide code provides the rationale for deciphering the communication code of human diseases and allows the interception of pathological interactions with maximum effectiveness.
2. Specificity. Peptide therapy enables maximum therapeutic specificity. Based on the precise understanding of the structure/function relation of specific protein signals, peptide therapy allows therapeutic targeting with unprecedented specificity.
3. Safety. Peptide therapy is extremely safe. The use of synthetic analogs to physiologic compounds essentially eliminates the problem of toxicity. Possible undesired biological side-effects should be controllable by optimizing the length and composition of the therapeutic peptide.
4. Savings in therapeutic research and development. Time and expenses for the development of therapeutic peptides is a fraction of conventional therapeutic research and development Identification of potential therapeutic peptides takes minutes; in vitro screening of potential peptides is a matter of weeks, animal studies should provide first in vivo results within a few months Most importantly the unprecedented specificity and safety background of peptide therapy will allow clinical studies without delay.
5. Advantage of peptide therapy compared to conventional therapies. The advantages of peptide therapy become even more obvious when this novel therapeutic approach is compared to conventional therapies or alternative future therapies. Conventional drug therapy is frequently compromised by an unknown therapeutic mechanism and by a wide range of side effects and considerable toxicity. Gene therapy is compromised by limited availability, its technological requirements and its high costs which restncts its therapeutic application to exclusive areas in the foreseeable future Heterologous or synthetic antibody therapy, the therapeutic application of antibodies produced outside of the patient's body, can cause incalculable adverse reactions by the patient's immune system against these 'foreign' antibodies. In contrast, peptide therapy makes elegant use of the patient's own immune system thereby excluding adverse immunological reactions.
V. Therapeutic Applications of Peptide Therapy
1. Infectious diseases. The most immediate application of peptide therapy is the prevention and treatment of infectious diseases. Every stage of any type of infectious disease is controlled by proteins which mediate adhesion, invasion and other mechanisms of pathogenicity Effective therapeutic interception of biological signals within these pathogenicity-mediating proteins must lead to the control of the infection itself. Table I lists some of the most frequent infectious diseases and potential target proteins for peptide therapy. As discussed above, therapeutic peptides can be applied in acute treatment of infectious diseases and as vaccines.
2. Neoplastic Diseases. Another area with immediate applications for peptide therapy is the treatment of neoplastic diseases Invasive growth and metastatic spread of any type of cancer is mediated by certain proteins and their signal sequences. Synthetic analogs to the signal sequences of these proteins should be developed as an effective therapy for different forms of cancer in their early stage as well as their invasive and metastatic stages.
3. Metabolic disorders. A novel therapeutic area for peptide therapy is the treatment of metabolic disorders. The potential of peptide therapy is exemplified here for the treatment of diabetes and hypertension.
Diabetes. Conventional diabetic therapy aims at an increased availability of insulin. Peptide therapy allows a novel and alternative approach by inhibiting the action of glucagon the insulin antagonist. The inhibition of glucagon can be accomplished by using the therapeutic peptides analogous to the glucagon signal sequence for direct competitive inhibition or as a vaccine (Figure 5).
Hypertension. The renin angiotensin system and particularly the angiotensin-converting enzyme (ACE) are a continuous focus of antihypertensive drug development. Renin, angiotensin I and II as well as ACE are also promising targets for peptide therapy. Therapeutic use of synthetic analogs to the signal sequences of any of these proteins will lead to decreased blood pressure. Since in most cases hypertension is a chronic condition the therapeutic use of renin, angiotensin or ACE signal peptide vaccines should be considered.
Signal Sequences from the following proteins as well as their use for diagnostic and therapeutic purposes are claimed in this patent:
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The following specific sequences are claimed in this patent: FARNESYL SYNTHETASE INFORMATION FOR SEQUENCE ID NO 1
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(B) TYPE: amino acid
(D) TOPOLOGY: linear
-R-K-F-Y-T-E-F-D-R-H-N-N-R- INFORMATION FOR SEQUENCE ID NO 348 (A) LENGTH:
(B) TYPE: amino acid
(D) TOPOLOGY: linear
-R-K-F-Y-T-E-F-D-R-H-N-N-R- CORTICOTROPIN RELEASING FACTOR BINDING PROTEIN INFORMATION FOR SEQUENCE ID NO 349
(A) LENGTH:
(B) TYPE: amino acid
(D) TOPOLOGY: linear
-R-Y-L-E-L-R-E-A-A-D-Y-D- INFORMATION FOR SEQUENCE ID NO 350
(A) LENGTH:
(B) TYPE: amino acid
(D) TOPOLOGY: linear
-R-Y-L-E-V-Q-E-A-A-V-Y-D- INFORMATION FOR SEQUENCE ID NO 351
(A) LENGTH:
(B) TYPE: amino acid
(D) TOPOLOGY: linear
-K-R-D-V-A-G-E-Q-P-Y-R-R- INFORMATION FOR SEQUENCE ID NO 352
(A) LENGTH:
(B) TYPE: amino acid
(D) TOPOLOGY: linear
-K-R-N-L-A-E-E-Q-P-Y-R-R- INFORMATION FOR SEQUENCE ID NO 353
(A) LENGTH:
(B) TYPE: amino acid
(D) TOPOLOGY: linear
-D-H-P-L-P-S-A-E-R- INFORMATION FOR SEQUENCE ID NO 354
(A) LENGTH:
(B) TYPE: amino acid
(D) TOPOLOGY: linear
-D-H-P-L-P-T-R-E-R- INFORMATION FOR SEQUENCE ID NO 355
(A) LENGTH:
(B) TYPE: amino acid
(D) TOPOLOGY: linear
-R-R-S-I-R-S-S-Q- INFORMATION FOR SEQUENCE ID NO 356
(A) LENGTH:
(B) TYPE: amino acid
(D) TOPOLOGY: linear
-R-R-S-V-T-S-S-Q- INFORMATION FOR SEQUENCE ID NO 367
(A) LENGTH:
(B) TYPE: amino acid
(D) TOPOLOGY: linear
-D-P-S-K-M-T-P-L-A-D- INFORMATION FOR SEQUENCE ID NO 358
(A) LENGTH:
(B) TYPE :amino acid
(D) TOPOLOGY: linear
-D-T-S-K-M-M-L-L-V-D- INFORMATION FOR SEQUENCE ID NO 359
(A) LENGTH:
(B) TYPE: amino acid
(D) TOPOLOGY: linear
-E-P-Y-E-L-E-N-P-N-G- INFORMATION FOR SEQUENCE ID NO 360
(A) LENGTH:
(B) TYPE: amino acid
(D) TOPOLOGY: linear
-E-P-L-E-L-E-T-S-T-R-

Claims

CLAIMS What is claimed is
1. A method to identify signal oligopeptides determining the action and interaction of a selected protein by determining the peptide regions of maximum hydrophylicity within the amino acid sequence (primary structure) of this protein. The regions of maximum hydrophylicity are identical with the signal oligopeptides of a protein.
2. A method to determine potential signal oligopeptides within a selected protein by use of a protein sequence database in combination with algorithms for hydrophylicity, and/or surface probability and/or other algorithms or their modifications as listed in Table 1 of this patent.
3. A method to identify, and develop xenologous signal oligopeptides as vaccines in the prevention and treatment of human diseases by making specific use of the technology described in detail in this patent. Effective vaccines to intercept the action of pathogenicity-mediating or undesired actions of selected human proteins can be produced by selecting the human protein, identifying the hydrophylicity peaks of this protein aligning this protein to the same proteins from other species, selecting the corresponding xenologous hydrophylicity peaks, developing immunogenic therapeutic peptides on the basis of these xenologous signal oligopeptides (For details see figures 1 ,3,5-7 and Table 2-3).
4. A method to titrate the therapeutic efficacy of xenologous signal oligopeptides by making use of the evolutionary clock: The greater the genetic and evolutionary distance of the selected animal species, the greater the variation of amino acid residues particularly within the signal sequence of these proteins, the greater the antigenicity of these signal sequences, and the greater the therapeutic clinical efficacy of synthetic oligopeptide vaccines identical with these xenologous signal oligopeptide sequences of a selected protein.
5. The use of the specific oligopeptide sequences No 1 to No 360 of this patent as well as of the specific① sequences of earlier patent applications with the serial numbers 07/997,734, 07/997,727, 08/045,394 for the design, development, and use of therapeutic and diagnostic agents in the following specific way: a) As therapeutic agents to function as direct competitive inhibitor(s) to specifically prevent or reduce the metabolic action or interaction of a selected protein by partially or completely blocking its specific signal sequences (For details see figure 1 ,2 and 6). b) As therapeutic agents to function as feed-back regulators to specifically prevent or reduce the synthesis rate a selected protein (For details see figure 1 and 4). c) As therapeutic agents in form of vaccines preferentially applied subcutaneously or intracutaneously with the aim to stimulate a specific immune response which can partially or completely block or decrease specific metabolic communication(s). Therapeutic peptides analogous to human protein sequences used
Figure imgf000085_0001
as vaccines could be coupled to haptens to enhance immune response and thereby therapeutic efficacy (For details see figure 1, 3, 5-7 and table 2-3). c) As vaccines for the production of specific and epitope-defined antibodies for in vitro use in a variety of diagnostic purposes (For details see figure 1 and 8).
6. Synthetic analogs to the specific oligopeptide sequences No 1 to No 360 of this patent, as well as of the specific sequences of earlier patent applications with the serial numbers 07/997,734; 07/997,727; 08/045,394 which vary from the sequences given in one or more of the following ways:
a) by omitting one or more of the amino residues at the N -terminal end (start of sequence given) b) by omitting one or more amino acid residues at the C-erminal end (end of the sequence give) c) by omitting one or more amino acid residues at the N-terminal and the C-terminal end of the sequence given
d) by substituting one or more of the amino acid residues within the given sequence without consideration of charge and polarity of the substitution residue
e) by substituting one or more of the amino acid residues within the given sequence with amino acid residues with similar charge and/or polarity
f) by omitting one or more amino acid residues within the given sequence
g) by a combination of two or more of the above modifications.
PCT/US1995/000575 1994-01-14 1995-01-12 Hydrophilic signal oligopeptides and methods of therapeutic use WO1995019568A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU16810/95A AU1681095A (en) 1994-01-14 1995-01-12 Hydrophilic signal oligopeptides and methods of therapeutic use
DK95908522T DK0744027T3 (en) 1994-01-14 1995-01-12 Use of methods for identifying hydrophilic signal oligopeptides
EP95908522A EP0744027B1 (en) 1994-01-14 1995-01-12 Use of methods for identifying hydrophilic signal oligopeptides
AT95908522T ATE291230T1 (en) 1994-01-14 1995-01-12 USE OF METHODS FOR IDENTIFYING HYDROPHILIC SIGNAL OLIGOPEPTIDES
DE69534077T DE69534077T2 (en) 1994-01-14 1995-01-12 USE OF METHODS FOR IDENTIFYING HYDROPHILIC SIGNAL OLIGOPEPTIDES
US10/930,300 US7300918B2 (en) 1994-01-14 2004-08-30 Method of producing vaccines from protein signal oligopeptides

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US18224894A 1994-01-14 1994-01-14
US08/182,248 1994-01-14

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Cited By (10)

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EP0804469A1 (en) * 1995-01-16 1997-11-05 Northern Sydney Area Health Service Novel peptide
WO1998003544A1 (en) * 1996-07-24 1998-01-29 Peptide Therapeutics Limited IDENTIFICATION OF SHORT PEPTIDE SEQUENCES REPRESENTING EPITOPES OF GLYCOPROTEIN G OF HSV-2 USING A PHAGE PEPTIDE DISPLAY LIBRARY FOR USE IN AN ANTI-gG2 ELISA
WO1998010787A2 (en) * 1996-09-11 1998-03-19 Prendergast Patrick T Pharmaceutical compositions for the treatment of immune disorders
WO2000071751A1 (en) * 1999-05-21 2000-11-30 Myriad Genetics, Inc. Diabetes gene
WO2003066672A1 (en) * 2002-02-08 2003-08-14 Nakoshi, Hideo Peptides
US6902888B1 (en) 1999-05-21 2005-06-07 Myriad Genetics, Inc. Diabetes gene
WO2009008888A1 (en) * 2007-07-10 2009-01-15 Matthias Rath African swine virus polypeptides as vaccines and its therapeutic use thereof
WO2014027049A1 (en) * 2012-08-14 2014-02-20 University Of Ulster Therapeutic uses of dogfish glucagon and analogues thereof
JP2018533570A (en) * 2015-10-21 2018-11-15 エイチオーエックス セラピューティクス リミテッド peptide
US11583576B2 (en) 2017-06-15 2023-02-21 Cancer Advances Inc. Compositions and methods for inducing humoral and cellular immunities against tumors and cancer

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WO1989005823A1 (en) * 1987-12-23 1989-06-29 The Upjohn Company Chimeric glycoproteins containing immunogenic segments of the glycoproteins of human respiratory syncytial virus
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US4554101A (en) * 1981-01-09 1985-11-19 New York Blood Center, Inc. Identification and preparation of epitopes on antigens and allergens on the basis of hydrophilicity
WO1989005823A1 (en) * 1987-12-23 1989-06-29 The Upjohn Company Chimeric glycoproteins containing immunogenic segments of the glycoproteins of human respiratory syncytial virus
WO1989010405A1 (en) * 1988-04-22 1989-11-02 The Upjohn Company Chimeric glycoproteins containig immunogenic segments of human parainfluenza virus type 3

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JOURNAL OF APPLIED NUTRITION, Volume 44, Numbers 3 & 4, issued 1992, RATH, "Cationic-Anionic and Anionic-Cationic Oligopeptides in Apoprotein-a and other Proteins as Modulators of Protein Action and of Biological Communication", pages 62-69. *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0804469A1 (en) * 1995-01-16 1997-11-05 Northern Sydney Area Health Service Novel peptide
EP0804469A4 (en) * 1995-01-16 1998-05-20 North Sydney Area Health Serv Novel peptide
US6057294A (en) * 1995-01-16 2000-05-02 Northern Sydney Area Health Service Of Pacific Highway Peptide
WO1998003544A1 (en) * 1996-07-24 1998-01-29 Peptide Therapeutics Limited IDENTIFICATION OF SHORT PEPTIDE SEQUENCES REPRESENTING EPITOPES OF GLYCOPROTEIN G OF HSV-2 USING A PHAGE PEPTIDE DISPLAY LIBRARY FOR USE IN AN ANTI-gG2 ELISA
WO1998010787A2 (en) * 1996-09-11 1998-03-19 Prendergast Patrick T Pharmaceutical compositions for the treatment of immune disorders
WO1998010787A3 (en) * 1996-09-11 1998-07-30 Patrick T Prendergast Pharmaceutical compositions for the treatment of immune disorders
WO2000071751A1 (en) * 1999-05-21 2000-11-30 Myriad Genetics, Inc. Diabetes gene
US6902888B1 (en) 1999-05-21 2005-06-07 Myriad Genetics, Inc. Diabetes gene
US7374884B2 (en) 1999-05-21 2008-05-20 Myriad Genetics, Inc. Diabetes gene
WO2003066672A1 (en) * 2002-02-08 2003-08-14 Nakoshi, Hideo Peptides
WO2009008888A1 (en) * 2007-07-10 2009-01-15 Matthias Rath African swine virus polypeptides as vaccines and its therapeutic use thereof
WO2014027049A1 (en) * 2012-08-14 2014-02-20 University Of Ulster Therapeutic uses of dogfish glucagon and analogues thereof
JP2018533570A (en) * 2015-10-21 2018-11-15 エイチオーエックス セラピューティクス リミテッド peptide
EP3610883A1 (en) * 2015-10-21 2020-02-19 Hox Therapeutics Limited Peptides
US11583576B2 (en) 2017-06-15 2023-02-21 Cancer Advances Inc. Compositions and methods for inducing humoral and cellular immunities against tumors and cancer

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ATE291230T1 (en) 2005-04-15
DE69536065D1 (en) 2010-05-27
EP1520859A2 (en) 2005-04-06
AU1681095A (en) 1995-08-01
ES2236703T3 (en) 2005-07-16
ATE464315T1 (en) 2010-04-15
DE69534077T2 (en) 2005-08-11
PT744027E (en) 2005-05-31
DK0744027T3 (en) 2005-06-13
EP0744027A1 (en) 1996-11-27
ES2344643T3 (en) 2010-09-02
EP1520859B9 (en) 2010-12-29
DE69534077D1 (en) 2005-04-21
EP0744027B1 (en) 2005-03-16

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