Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/08—Peptides having 5 to 11 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• This invention relates to an antiviral treatment that inhibits viral replication by altering
• immediate gene expression in infected cells and also to a method for regulating immediate gene
• Peptide T and its analogs has been found helpful in counteracting some of the symptoms of AIDS, by inhibiting the binding of HIV antigen to CD4 receptors. See U.S. Patent Nos.
• Peptide T has also been suggested to inhibit gpl20 induced increases in somatostatin that may
• Mammalian viruses typically have immediate early genes which are necessary for
• immediate early genes are defined by their transciption after infection in the
• JC virus uses a temporal pathway where synthesis of virus encoded
• proteins is divided into the expression of early and late genes based on their temporal
• T antigen expression occurs early in the virus cycle under control of the viral enhancer/promoter region. Synthesis of T antigen then initiates viral DNA
• IEG's Host cell immediate early genes
• IEG's are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors which are nuclear transcription factors
• Nuclear transcription factors involved in the immediate early response are:
• IEG'S serving as host cell transcription factors can alter host cell responses to extra cellular
• IEG's have been implicated in many of the changes in nervous system function mediated
• neurotransmitters by neurotransmitters, neuromodulators and hormones, and IEG's may be influenced by drug
• IEG'S insulin mediated by IEG'S.
• c-fos and c-jun are involved in the growth hormone induced release of neuropeptide Y and somatastatin.
• IEG induction of IEG expression.
• IEG's mediate expression of early-delayed and late gene expression in the post-synaptic neuron.
• IEG's have also been implicated in the pathophysiologic response to cell injury, due to
• IEG responses have been shown to be important in
• immunomodulators such as lipopolysaccharide
• IEG's in apoptosis appears to be a major pathway for cell death in neurodegenerative disorders. IEG's appear to be involved in the regulation of neurothrophic factor expression in the
• Neurotrophic factors play a significant role in other diseases of the nervous
• Alzheimer's disease a degenerative diseases of the human nervous system including Alzheimer's disease,
• neurothrophic factors occur in temporal lobe epilepsy, the most common adult seizure disorder.
• Circulating hormones have been found to regulate neurotrophic factor expression and release by
• NGF glial cells and neurons.
• BDNF BDNF and NT3 expression is up-regulated by growth hormone and cortisol. Preliminary experiments suggest that thyroid hormone may also control
• Egr-3 and possibly Egr-1, are involved in the regulation of
• IEG's are implicated in so many different physiologic or neurologic disorders and in normal
• IGE's expressed by the cell holds considerable promise as a therapeutic agent in a
• the invention is a method of treating viral
• R a Ser-Thr-Thr-Thr-Asn-Tyr-R b
• R a represents an amino terminal residue Ala- or D- Ala and R represents a carboxy
• Rl is an amino terminal residue Thr-, Ser-, Asn-, Glu-, Arg-, He- or Leu-, R2 is Thr, Ser,
• R3 is Thr, Ser, Asn, Arg, Gin, Lys, or Trp
• R4 is Tyr and R5 is preferably a carboxy
• Fig. 1 is a graph showing c-jun expression in peptide T treated cells.
• Fig. 2 is a graph showing c-jun expression in peptide T treated cells and infected/treated
• Fig. 3 is a graph showing c-jun expression in control and infected cells.
• Fig. 4 is a graph showing c-jun expression in peptide T treated cells.
• Fig. 5 is a graph showing egr-1 expression in peptide T treated cells.
• Fig. 6 is a graph showing egr-1 expression in control and infected cells.
• Fig. 7 is a graph showing egr-1 expression in peptide T treated cells and infected/treated
• this invention is directed to a peptide of the formula (I): R a -Ser-Thr-Thr-Thr-Asn-Tyr-R b
• R a represents an amino terminal residue Ala- or D- Ala and R b represents a carboxy
• Rl is an amino terminal residue Thr-, Ser-, Asn-, Glu-, Arg-, He- or Leu-, R2 is Thr, Ser,
• R3 is Thr, Ser, Asn, Arg, Gin, Lys, or Trp
• R4 is Tyr and R5 is preferably a carboxy
• amino acid at the R5 position may vary widely.
• the compounds of the invention may be beneficially modified by known methods to enhance passage across the blood-brain barrier, improve stability and/or oral availability.
• the inventive method involves treating diseases and conditions by regulating immediate early
• R a Ser-Thr-Thr-Thr-Asn-Tyr-R b
• R a represents an amino terminal residue Ala- or D- Ala
• R b represents a carboxy
• R1-R2-R3-R4-R5 where Rl is an amino terminal residue Thr-, Ser-, Asn-, Glu-, Arg-, He- or Leu-, R2 is Thr, Ser,
• R3 is Thr, Ser, Asn, Arg, Gin, Lys, or Trp
• R4 is Tyr and R5 is preferably a carboxy
• the method may further utilize a peptide selected from the group consisting of D- Ala-
• the peptide can be
• parenteral topical, rectal, transdermal or intranasal administration.
• the topical topical, rectal, transdermal or intranasal administration.
• the transdermal or intranasal administration in one embodiment, the
• peptide is administered daily and parenterally at from 0.2-10 mg/kg for a 70 kg human, and can
• the peptide T may be delivered parenterally,. especially
• Peptide T may be dried and administered intranasally by being
• composition of the invention is normally formulated in a physiologically acceptable
• composition may contain from 0.001-99% of the peptide T.
• compositions may also contain other active ingredients, such as antimicrobials, and the like.
• inventions are not limited in this way. They may also be formulated as powders, granules, tablets,
• formulations may be packaged in single or multidose form.
• U87MG cells were cultured in media containing Peptide T at 10 and 0.01 ⁇ g/ml.
• the viral enhancer/promoter region has three
• NF-ID is essential for virus enhancer/promoter
• JCV infected U87MG cells were treated with Peptide T at 10 ⁇ g and
• the JC virus enhancer / promoter has a number of binding sites recognized by host cell
• JC virus enhancer/promoter activity by forming a nuclear transcription factor complex with NF-
• T antigen the pivotal virus protein which controls the virus replication.
• Peptide T blocks JC virus T antigen synthesis and therefore virus replication.
• Control cultures were sham treated with vehicle used to dissolve Peptide T in
• JC virus infected cells U87MG cells treated with Peptide T have a
• JC virus infected U87MG cells treated with Peptide T at 10 ⁇ g/ml express less of a rise in egr-1 activity than cells treated with 0.01
• Peptide T blocks expression of egr-1 at 16 hours in JC virus infected U87MG cells.
• Peptide T also induces expression of egr-1 in virus infected cells at 4 hours but not to the level of stimulated control cells. The stimulation of egr-1 in Peptide T treated
• the egr family of transcription factors has several members that are up-regulated at varying
• Egr-1 stimulates the synthesis of egr-3 that follows several hours after egr-1 expression.
• immediate-delayed and delayed genes which could be affected by alteration in egr-1 expression include
• TL-1 immunomodulatory molecules
• IL-2 immunomodulatory molecules
• TNF- ⁇ TGF- ⁇
• TGF- ⁇ neurotrophic factors
• BDNF BDNF, NT3, NT4/5
• BDNF BDNF, NT3, NT4/5
• Egr-3 is a second member of the egr family of transcription factors involved in IEG
• infected cells have a transient increase in expression of egr-3 at 1 hr. post infection. Egr-3 levels
• Egr-3 is up regulated and sustained for 96 hours in
• Peptide T treated, uninfected U87MG cells. Levels of egr-3 were 10X increased in cells treated
• Peptide T inhibits JCV replication in vitro in both continuous and primary glial
• Peptide T reduces c-jun expression at 4 hours in uninfected cells; blocks up-regulation of c-jun expression induced by
• JC virus infected U87MG cells and blocks egr-1 up-regulation by JC virus at 16 hours.
• infected or uninfected U87MG cells is not altered by Peptide T.
• Peptide T in JC virus infected cells which can have application to the treatment of other viral diseases.
• the alterations of IEG expression demonstrate Peptide T is able to signal glial cells to
• transcription factors i.e. egr-3, NF-ID, etc.
• immunomodulators cytokines
• neurotrophic factors i.e. IL-4, IL-6, etc.
• virus expression i.e. Herpes simplex, Varicella zoster, etc.
• RNA viruses which use host cell transcription factors RNA viruses which use host cell transcription factors
• RNA viruses under strict virus encoded molecular control HTLV-1, 2
• Peptide T does not halt infection, it may have a synergistic effect when used with other drugs if it blocks or alters transcriptional activity of host cells.
• autoimmune disorders multiple sclerosis
• neurohormonal disorders growth hormone
• neurotrophic factors which may include, for example, Alzheimers' disease.
• Degenerative neurotrophic factors which may include, for example, Alzheimers' disease.
• mRNA transcript changes in drug treated cells.
• Peptide T to treat neurohormonal disorders and the expression of neurotropic factors that are regulated by

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Veterinary Medicine (AREA)
• Immunology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Biomedical Technology (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Epidemiology (AREA)
• Gastroenterology & Hepatology (AREA)
• Transplantation (AREA)
• Virology (AREA)
• Hospice & Palliative Care (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Psychiatry (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Peptides Or Proteins (AREA)

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Publications (2)

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Citations (2)

• 2000
  • 2000-11-09 EP EP00990995A patent/EP1242109A4/de not_active Withdrawn
  • 2000-11-09 WO PCT/US2000/042030 patent/WO2001034095A2/en not_active Application Discontinuation
  • 2000-11-09 KR KR1020027006014A patent/KR20020063182A/ko not_active Application Discontinuation
  • 2000-11-09 CN CNA008154821A patent/CN1635913A/zh active Pending
  • 2000-11-09 CA CA002389392A patent/CA2389392A1/en not_active Abandoned
  • 2000-11-09 IL IL14944300A patent/IL149443A0/xx unknown
  • 2000-11-09 JP JP2001536100A patent/JP2003528817A/ja active Pending
  • 2000-11-09 AU AU30800/01A patent/AU3080001A/en not_active Abandoned
  • 2000-11-09 MX MXPA02004619A patent/MXPA02004619A/es unknown
• 2002
  • 2002-04-19 ZA ZA200203120A patent/ZA200203120B/en unknown

Patent Citations (2)

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