WO2022054826A1 - Agent antiviral - Google Patents

Agent antiviral Download PDF

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Publication number
WO2022054826A1
WO2022054826A1 PCT/JP2021/032971 JP2021032971W WO2022054826A1 WO 2022054826 A1 WO2022054826 A1 WO 2022054826A1 JP 2021032971 W JP2021032971 W JP 2021032971W WO 2022054826 A1 WO2022054826 A1 WO 2022054826A1
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peptide
amino acid
group
acid sequence
viral
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PCT/JP2021/032971
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English (en)
Japanese (ja)
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和雄 北村
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国立大学法人宮崎大学
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Priority to JP2022547618A priority Critical patent/JPWO2022054826A1/ja
Publication of WO2022054826A1 publication Critical patent/WO2022054826A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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
    • C07K14/575—Hormones
    • 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

  • the present invention relates to an antiviral agent.
  • one aspect of the present invention relates to an antiviral agent containing adrenomedullin or a derivative thereof as an active ingredient.
  • COVID-19 infectious diseases caused by the new coronavirus (hereinafter, also referred to as "SARS-CoV-2”) (hereinafter, also referred to as "COVID-19”) have become widespread worldwide. COVID-19 is also said to be severe in a certain proportion of patients. Therefore, in the treatment of COVID-19 patients, lifesaving of critically ill patients has become a very important issue. In COVID-19, the mortality rate of patients with severe pneumonia is high. In addition, there are some situations that cannot be dealt with by conventional antiviral drugs that are currently being researched.
  • SARS-CoV-2 various viruses such as influenza virus and severe acute respiratory syndrome (hereinafter, also referred to as "SARS") coronavirus have caused pandemics. These viral infections have caused organ damage from systemic inflammation, resulting in the loss of many lives.
  • SARS severe acute respiratory syndrome
  • Adrenomedullin (hereinafter, also referred to as "AM”) is a bioactive peptide isolated and identified from brown cell tissue in 1993 (Non-Patent Document 1). Initially discovered, AM was found to exert a strong vasodilatory antihypertensive effect. For example, Patent Document 1 describes a peptide having a blood pressure lowering effect, which comprises an amino acid sequence of human AM.
  • AM exerts various pharmacological actions such as cardiovascular protective action, anti-inflammatory action, angiogenic action, tissue repair promoting action and organ protective action.
  • administration studies of AM to patients with various diseases have been conducted with the aim of applying the pharmacological action of AM to the treatment of diseases.
  • the usefulness of AM as a therapeutic agent for inflammatory bowel disease, pulmonary hypertension or peripheral vascular disease is expected.
  • Patent Document 2 describes an adrenomedullin or a derivative thereof having an activity of suppressing non-bacterial inflammation, or a salt thereof having an activity of suppressing non-bacterial inflammation as an active ingredient. Describes a prophylactic or therapeutic agent for non-bacterial inflammatory bowel disease contained as.
  • Patent Document 3 describes the method for preventing or treating an inflammatory bowel disease in a patient who requires the prevention or treatment of an inflammatory bowel disease in which the use of a steroid preparation, an immunosuppressive agent or a biological preparation is difficult or inadequate.
  • the present invention comprises administering to the patient an effective amount of adrenomedulin, a derivative thereof having an activity of suppressing inflammation, or a salt of the adrenomedulin or the derivative thereof having an activity of suppressing inflammation.
  • the prevention or treatment method is described.
  • Adrenomedullin a novel hypotensive peptide isolated from human pheochromocytoma. , Pp. 553-560
  • viruses including SARS-CoV-2 and influenza virus are known as viruses that cause viral infections.
  • effective therapeutic agents have not yet been established, except for a few viruses such as influenza virus and herpesvirus.
  • viral infections caused by influenza virus, varicella-zoster virus and measles virus can be expected to be prevented by vaccination against each virus.
  • influenza virus many people are affected and die worldwide every year. In Japan as well, thousands of people die each year from viral infections caused by the influenza virus. For this reason, there has been a demand for new therapeutic means for viral infections that can become severe.
  • AM cardiovascular protective action, anti-inflammatory action, angiogenic action, tissue repair promoting action, organ protecting action, etc. are known. However, the antiviral effect of AM was not known.
  • the present inventor has examined various means for solving the above problems.
  • the present inventor has found that AM has antiviral activity against specific viruses that cause viral infections.
  • the present inventor has completed the present invention based on the above findings.
  • an antiviral agent containing adrenomedullin or a derivative thereof as an active ingredient containing adrenomedullin or a derivative thereof as an active ingredient.
  • the adrenomedullin or its derivative is as follows: (I) A peptide consisting of the amino acid sequence of adrenomedulin, (Ii) A peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine residues in the amino acid sequence form a disulfide bond.
  • An organic group selected from the group consisting of a modifying group containing a C 4 -C 30 alkyl group, a C 4 -C 30 alkenyl group or a polyethylene glycol group, an Fc region of an immunoglobulin, and a serum albumin in the ⁇ -amino group is selected.
  • the adrenomedullin or its derivative is as follows: (I) A peptide consisting of the amino acid sequence of adrenomedulin, (Ii) A peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine residues in the amino acid sequence form a disulfide bond. (V) In the peptide of (i) or (ii), the peptide in which the C-terminal is amidated, (Vi) In the peptide of (i) or (ii), the peptide having a glycine residue added to the C-terminal, and any of (vii) (i), (ii), (v) and (vi).
  • the antiviral agent according to embodiment (2) which is a peptide or compound selected from the group consisting of.
  • the adrenomedullin or its derivative is as follows: (A) A peptide consisting of the amino acid sequence of SEQ ID NO: 1 or a peptide consisting of the amino acid sequence of SEQ ID NO: 1 and in which the cysteine residue at position 16 and the cysteine residue at position 21 form a disulfide bond; (B) A peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4 and in which the cysteine residue at position 16 and the cysteine residue at position 21 form a disulfide bond; (C) A peptide consisting of the amino acid sequence of SEQ ID NO: 6 or a peptide consisting of the amino acid sequence of SEQ ID NO: 6 in which the cysteine residue at position 16 and the cysteine residue at position 21 form a disulfide bond; (D) A peptide consisting of the amino acid sequence of SEQ ID NO: 8 or a peptide consist
  • An organic group selected from the group consisting of a modifying group containing a C 4 -C 30 alkyl group, a C 4 -C 30 alkenyl group or a polyethylene glycol group, an Fc region of an immunoglobulin, and a serum albumin in the ⁇ -amino group is selected.
  • the adrenomedullin or its derivative is as follows: (A) A peptide consisting of the amino acid sequence of SEQ ID NO: 1 or a peptide consisting of the amino acid sequence of SEQ ID NO: 1 and in which the cysteine residue at position 16 and the cysteine residue at position 21 form a disulfide bond; (B) A peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4 and in which the cysteine residue at position 16 and the cysteine residue at position 21 form a disulfide bond; (C) A peptide consisting of the amino acid sequence of SEQ ID NO: 6 or a peptide consisting of the amino acid sequence of SEQ ID NO: 6 in which the cysteine residue at position 16 and the cysteine residue at position 21 form a disulfide bond; (D) A peptide consisting of the amino acid sequence of SEQ ID NO: 8 or a peptide consist
  • the antiviral agent according to embodiment (4) which is a peptide or compound selected from the group consisting of.
  • the peptide (iv) in the adrenomedullin or a derivative thereof is a peptide in which 1 to 3 amino acid residues are substituted or deleted in the peptide consisting of the amino acid sequence of SEQ ID NO: 14.
  • the adrenomedulin or a derivative thereof has the amino acid sequence of SEQ ID NO: 17, the C-terminal is amidated, and the cysteine residue at the 4-position and the cysteine residue at the 9-position form a disulfide bond.
  • New coronavirus SARS-CoV-2
  • severe acute respiratory syndrome SARS
  • MERS Middle East respiratory syndrome
  • normal human coronavirus 229E, NL63, OC43 and HKU1
  • viruses selected from the group consisting of influenza virus, dengue virus, RS virus, adenovirus, varicella / herpes zoster virus, simple herpes virus, measles virus, parainfluenza virus, enterovirus, rhinovirus and human metapneumovirus.
  • the antiviral agent according to any one of the above-described embodiments (1) to (8), which is applied.
  • Viral infections caused by the virus include viral pneumonia, viral myocarditis, viral encephalitis, viral hemorrhagic fever, viral nephropathy, viral gastroenteritis, viral vasculitis, and viral stomatitis.
  • a pharmaceutical composition for preventing or treating a symptom or disorder in a subject having a viral infection which comprises a pharmaceutically acceptable carrier of the above.
  • the viral infections include new coronavirus (SARS-CoV-2), severe acute respiratory syndrome (SARS) coronavirus, Middle East respiratory syndrome (MERS) coronavirus, and normal human coronavirus (229E,). Selected from the group consisting of NL63, OC43 and HKU1), influenza virus, dengue virus, RS virus, adenovirus, varicella / herpes zoster virus, simple herpes virus, measles virus, parainfluenza virus, enterovirus, rhinovirus and human metapneumovirus.
  • SARS-CoV-2 new coronavirus
  • SARS severe acute respiratory syndrome
  • MERS Middle East respiratory syndrome
  • 229E normal human coronavirus
  • the viral infection is viral pneumonia, viral myocarditis, viral encephalitis, viral hemorrhagic fever, viral nephropathy, viral gastroenteritis, viral vasculitis, viral stomatitis, viral corneal.
  • a method for preventing or treating a symptom or disorder of the viral infection which comprises administering the antiviral agent according to the above.
  • the viral infections include new coronavirus (SARS-CoV-2), severe acute respiratory syndrome (SARS) coronavirus, Middle East respiratory syndrome (MERS) coronavirus, and normal human coronavirus (229E,). Selected from the group consisting of NL63, OC43 and HKU1), influenza virus, dengue virus, RS virus, adenovirus, varicella / herpes zoster virus, simple herpes virus, measles virus, parainfluenza virus, enterovirus, rhinovirus and human metapneumovirus.
  • SARS-CoV-2 new coronavirus
  • SARS severe acute respiratory syndrome
  • MERS Middle East respiratory syndrome
  • 229E normal human coronavirus
  • the viral infection is viral pneumonia, viral myocarditis, viral encephalitis, viral hemorrhagic fever, viral nephropathy, viral gastroenteritis, viral vasculitis, viral stomatitis, viral corneal.
  • the antiviral agent according to any one of (10).
  • the viral infections include new coronavirus (SARS-CoV-2), severe acute respiratory syndrome (SARS) coronavirus, Middle East respiratory syndrome (MERS) coronavirus, and normal human coronavirus (229E,). Selected from the group consisting of NL63, OC43 and HKU1), influenza virus, dengue virus, RS virus, adenovirus, varicella / herpes zoster virus, simple herpes virus, measles virus, parainfluenza virus, enterovirus, rhinovirus and human metapneumovirus.
  • SARS-CoV-2 new coronavirus
  • SARS severe acute respiratory syndrome
  • MERS Middle East respiratory syndrome
  • 229E normal human coronavirus
  • influenza virus dengue virus, RS virus, adenovirus, varicella / herpes zoster virus, simple herpes virus, measles virus, parainfluenza virus, enterovirus
  • the viral infection is viral pneumonia, viral myocarditis, viral encephalitis, viral hemorrhagic fever, viral nephropathy, viral gastroenteritis, viral vasculitis, viral stomatitis, viral corneal.
  • the viral infections include new coronavirus (SARS-CoV-2), severe acute respiratory syndrome (SARS) coronavirus, Middle East respiratory syndrome (MERS) coronavirus, and normal human coronavirus (229E,).
  • NL63, OC43 and HKU1 Selected from the group consisting of NL63, OC43 and HKU1
  • influenza virus dengue virus, RS virus, adenovirus, varicella / herpes zoster virus, simple herpes virus, measles virus, parainfluenza virus, enterovirus, rhinovirus and human metapneumovirus.
  • the viral infection is viral pneumonia, viral myocarditis, viral encephalitis, viral hemorrhagic fever, viral nephropathy, viral gastroenteritis, viral vasculitis, viral stomatitis, viral corneal.
  • FIG. 1 is a graph showing the relationship between the concentration of adrenomedullin added to various viruses and the number of plaques formed in Test I.
  • the horizontal axis is the added adrenomedullin concentration (M)
  • the vertical axis is the number of plaques formed in each well.
  • AM Adrenomedullin
  • one aspect of the present invention relates to an antiviral agent containing adrenomedullin or a derivative of adrenomedullin (hereinafter, may be referred to as "adrenomedullin or a derivative thereof") as an active ingredient.
  • the "derivative of adrenomedullin” has adrenomedullin activity.
  • a part of the peptide consisting of the amino acid sequence of adrenomedullin is deleted, substituted, or added to the "adrenomedullin or a derivative thereof.
  • Adrenomedullin analog a peptide consisting of an adrenomedullin amino acid sequence or a peptide in which two cysteine residues in the amino acid sequence form a disulfide bond, or the disulfide bond is replaced by an ethylene group.
  • Peptides include compounds having a peptide chain corresponding to AM or a peptide chain corresponding to an AM analog in its partial structure.
  • the adrenomedullin activity means various physiological actions exemplified by the following (1) to (11), and in particular, a symptom or disorder of a viral infection such as an antiviral action possessed by AM. It means a physiological action that can be involved in prevention or treatment.
  • the adrenomedulin activity further refers to, for example, the action of binding to the adrenomedullin receptor (CLR / RAMP2 or CLR / RAMP3) in the subject and increasing the amount of cAMP in the subject, and the adrenomedullin receptor (CLR / RAMP2 or CLR /) in the subject. It also means the action of binding to RAMP3) and causing biological activity in the subject.
  • the medicine of this embodiment has a biological activity (that is, adrenomedulin activity) substantially equivalent to that of the natural adrenomedulin, and is used for a viral infection. It is possible to prevent or treat the symptoms or disorders of a viral infection in a subject having, for example, a human patient having a viral infection.
  • Cardiovascular system Vascular dilation action, blood pressure lowering action, blood pressure rise suppressing action, heart rate increase / heart failure improving action, pulmonary hypertension improving action, angiogenesis action, lymphangiogenesis action , Vascular endothelial function improving action, vascular permeability control, endothelial cell adhesion control, vascular endothelial barrier protective action, anti-arteriosclerotic action, myocardial protective action (eg, myocardial protective action in ischemia-reperfusion injury or inflammation), myocardial infarction Subsequent remodeling inhibitory effect, cardiac hypertrophy inhibitory effect, and angiotensin converting enzyme inhibitory effect.
  • myocardial protective action eg, myocardial protective action in ischemia-reperfusion injury or inflammation
  • Kidney / water electrolyte system diuretic effect, sodium diuretic effect, antidiuretic hormone inhibitory effect, aldosterone lowering effect, renal protective effect (for example, myocardial protective effect in hypertension or ischemia-reperfusion injury), diabetic nephropathy suppression Action, C3 nephropathy suppressing action, drinking behavior suppressing action, and salt demand suppressing action.
  • Brain / nervous system Neuroprotective / cerebral disorder inhibitory effect, anti-inflammatory effect, apoptosis inhibitory effect (for example, ischemia-reperfusion injury or apoptosis inhibitory effect in inflammation), autoregulatory ability maintenance effect, oxidative stress inhibitory effect, Dementia improving effect and sympathetic depressant effect.
  • Genitourinary system erection improving action, blood flow improving action, and implantation promoting action.
  • Digestive system anti-ulcer action, tissue repair action, mucosal neoplastic action, intestinal barrier protection action, blood flow improving action, anti-inflammatory action, and liver function improving action.
  • Orthopedic system Osteoblast stimulating action and arthritis improving action.
  • Endocrine metabolism system adipocyte differentiation action, lipolysis control action, insulin sensitivity improving action, insulin secretion control action, antidiuretic hormone secretion inhibitory action, and aldosterone secretion inhibitory action.
  • Respiratory system Bronchial dilation effect, lung protection effect, emphysema improving effect, pulmonary fibrosis suppression, pneumonia suppression, bronchitis suppression effect, and respiratory improvement effect.
  • Immune system C3b degradation promoting action.
  • Others Circulation improving action, anti-inflammatory action, cytokine control action, organ protection action, oxidative stress suppressing action, tissue repair action (for example, anti-decubitus action), sepsis improving action, septic shock improving action, many Suppressive action of organ failure, suppressive action of autoimmune disease, suppressive action of diabetic retinopathy, antibacterial action, hair growth action, and hair nourishing action.
  • the virus to which the antiviral agent is applied includes, for example, a new type coronavirus (SARS-CoV-2), a severe acute respiratory syndrome (SARS) coronavirus, and a Middle East respiratory syndrome (hereinafter referred to as “)”.
  • SARS-CoV-2 new type coronavirus
  • SARS severe acute respiratory syndrome coronavirus
  • MERS Middle East respiratory syndrome
  • Coronavirus also referred to as "MERS"
  • MERS normal human coronavirus
  • influenza virus normal human coronavirus (229E, NL63, OC43 and HKU1)
  • influenza virus dengue virus
  • RS virus normal human coronavirus
  • adenovirus varicella / herpes zoster virus
  • simple herpesvirus simple herpesvirus
  • measles virus para
  • viruses selected from the group consisting of influenza virus, enterovirus, rhinovirus and human metapneumovirus can be mentioned, and in particular, one or more selected from the group consisting of SARS-CoV-2 and influenza virus.
  • Virus can be mentioned.
  • effective therapeutic agents have not yet been established except for a few viruses such as influenza virus and herpesvirus.
  • AM or a derivative thereof which is the active ingredient of the antiviral agent of this embodiment, has an antiviral effect against these viruses. Therefore, by applying the antiviral agent of this embodiment to the virus exemplified above, an antiviral effect such as growth inhibition, inactivation and / or death is exhibited in vitro or in vivo. can do.
  • the antiviral agent of this embodiment by administering the antiviral agent of this embodiment to a subject having a viral infection caused by the virus exemplified above, for example, a human patient having a viral infection, the antiviral action of AM or a derivative thereof is mediated. Can prevent or treat the symptoms or disorders of viral infections.
  • the viral infection caused by the virus exemplified above is not limited, for example, viral pneumonia, viral myocarditis, viral encephalitis, viral hemorrhagic fever, virus.
  • Nephropathy, viral gastroenteritis, viral vasculitis, viral stomatitis, viral keratitis and viral neuritis can be mentioned, especially viral pneumonia.
  • Viral pneumonia in subjects with viral pneumonia, such as human patients with viral pneumonia is usually severe viral pneumonia, especially severe viral pneumonia requiring mechanical ventilation.
  • severe pneumonia means pneumonia in which symptoms such as respiratory failure are confirmed.
  • mechanical ventilation means mechanically ensuring breathing using a ventilator.
  • the antiviral agent of this embodiment by administering the antiviral agent of this embodiment to a subject having the viral infection exemplified above, for example, a human patient having the viral infection, the antiviral action of AM or a derivative thereof can be exhibited. Through it, the symptoms or disorders of viral infections can be prevented or treated.
  • the symptoms or disorders of the viral infection in a subject having the viral infection are not limited, but for example, in the case of viral pneumonia, organ disorder, respiratory disorder. (Eg coughing or difficulty breathing, etc.), fever, muscle pain, general malaise, sepsis, septic shock, and multi-organ failure (eg lung, kidney, liver, heart, blood vessel or cerebral nerve organ failure); viral myocardium For inflammation, myocarditis; for viral encephalitis, encephalitis; for viral hemorrhagic fever, hemorrhagic fever; for viral nephropathy, nephropathy; for viral gastroenteritis, gastroenteritis; In the case of viral vasculitis, vasculitis; in the case of viral stomatitis, stomatitis; in the case of viral keratitis, keratitis; and in the case of viral neuritis, neuritis can be mentioned.
  • the antiviral agent of this embodiment by administering the antiviral agent of this embodiment to a subject having a viral infection, for example, a human patient having a viral infection, the antiviral action of AM or a derivative thereof is used. It is possible to obtain the preventive or therapeutic effect of the symptom or disorder of the viral infection exemplified in.
  • Undesirable serious side effects that can occur when administering AM or a derivative thereof to a subject with a viral infection, such as a human patient with a viral infection, are, but are not limited to, for example, excessive blood pressure. Circulatory insufficiency (shock) due to a decrease can be mentioned.
  • administration of the antiviral agent of this aspect to a subject having a viral infection, eg, a human patient with a viral infection causes the unwanted and serious side effects exemplified above. Can prevent or treat the symptoms or disorders of viral infections.
  • the antiviral effect of AM or its derivatives is, for example, culturing a virus and its host cells in the presence of AM or its derivatives to suppress growth against the virus (eg, suppress plaque formation). It can be determined by assessing inactivation and / or death. Alternatively, it can be determined by administering AM or a derivative thereof to a virus-infected subject, for example, a human patient, and measuring the virus concentration in the subject's body.
  • the prophylactic or therapeutic effect of a viral infection symptom or disorder in a subject having a viral infection is such that the subject has a viral infection.
  • the antiviral agent of this embodiment is administered to determine the symptoms or disorders of a viral infection in the subject, eg, a treatment period (eg, a period requiring mechanical ventilation), a clinical condition, a clinical test (eg, hematology).
  • Tests and blood biochemical tests), vital signs (eg blood pressure and heart rate), and inflammatory cytokines (eg IL-1 ⁇ , IL-6, IL-8, IL-10, TNF- ⁇ , IFN- ⁇ ) , Autotaxin, FDP, D-Dimer, tPA, PIC and PTX3) can be determined by evaluation using the indicators.
  • the prophylactic or therapeutic effect of a viral infection symptom or disorder in a subject having a viral infection eg, a human patient with a viral infection
  • undesired serious side effects when the antiviral agent of this embodiment is administered to a subject having a viral infection, for example, a human patient having a viral infection.
  • the occurrence of circulatory insufficiency (shock), etc. due to a decrease in blood pressure can be determined, for example, by observing hemodynamics such as blood pressure.
  • prevention means substantially preventing the occurrence (onset or manifestation) of a symptom or disorder in a subject having a viral infection, for example, a human patient having a viral infection.
  • treatment suppresses (for example, suppression of progression) an onset (onset or manifestation) of a symptom or disorder in a subject having a viral infection, for example, a human patient having a viral infection. Means remission, repair and / or healing.
  • AM is not only a human-derived peptide isolated and identified from human brown cell tissue (SEQ ID NO: 1, Non-Patent Document 1), but also, for example, pig (SEQ ID NO: 4), dog (SEQ ID NO: 4). It may be a peptide (ortholog) derived from other non-human mammals (eg, warm-blooded animals) such as No. 6), bovine (SEQ ID NO: 8), rat (SEQ ID NO: 10) or mouse (SEQ ID NO: 12). In vivo, these peptides have two cysteine residues in their amino acid sequence forming a disulfide bond and the C-terminus being amidated.
  • the peptide having a disulfide bond and a C-terminal amide group may be referred to as "natural adrenomedullin” or simply “adrenomedullin”.
  • any of the above peptides can be applied as an active ingredient.
  • C-terminal amidation means an aspect of post-translational modification of a peptide in vivo, and specifically, the main chain carboxyl group of the C-terminal amino acid residue of the peptide is an amide group. It means a reaction that is transformed into a form.
  • formation of a disulfide bond of a cysteine residue or “disulfide formation of a cysteine residue” means one aspect of post-translational modification of a peptide in vivo, and specifically, the peptide. It means a reaction in which two cysteine residues in an amino acid sequence form a disulfide bond (-SS-).
  • bioactive peptides produced in vivo are initially biosynthesized as higher molecular weight precursor proteins, such as C-terminal amidation and / or cysteine residue disulfide during intracellular translocation. After translation, it undergoes a modification reaction to become a mature physiologically active peptide.
  • C-terminal amidation usually proceeds by the action of C-terminal amyloid enzyme on precursor protein.
  • a physiologically active peptide having a C-terminal amide group in the precursor protein, a Gly residue is bound to the C-terminal carboxyl group to be amidated, and the Gly residue is C-terminal by the C-terminal amidase. Converted to an amide group.
  • the C-terminal propeptide of precursor protein contains a repeating sequence of a combination of basic amino acid residues such as Lys-Arg or Arg-Arg (Mizuno, Biochemistry Vol. 61, No. 12, No. 12). Pp. 1435-1461 (1989)).
  • Disulfide formation of cysteine residues can proceed under oxidative conditions. In vivo, disulfide formation of cysteine residues usually proceeds by the action of protein disulfide isomerase on the precursor protein.
  • the "adrenomedullin derivative” or “adrenomedullin derivative” also includes a compound having a peptide chain corresponding to AM or an AM analog in its partial structure.
  • the compound having a peptide chain or AM analog corresponding to AM in its partial structure include compounds in which an appropriate organic group is attached to the N-terminal ⁇ -amino group with or without a linking group. ..
  • the organic group includes, but is not limited to, a modifying group containing a C 4 -C 30 alkyl group, a C 4 -C 30 alkenyl group or a polyethylene glycol group, an Fc region of immunoglobulin, serum albumin and the like.
  • Specific examples thereof include, for example, an amide-linked long-acting adrenomedullin derivative disclosed in International Publication No. 2015/14 189, and the specification of International Publication No. 2017/047788.
  • serum albumin-linked long-acting adrenomedulin derivatives disclosed in the specification of PCT / JP2021 / 21112.
  • the novel adrenomedullin analog disclosed in the specification of PCT / JP2021 / 14296 before publication of the application is also included in the AM derivative having the adrenomedullin activity of each aspect of the present invention.
  • the method for preparing the AM derivative include a method of purchasing the commercially available AM derivative, a method of applying an appropriate conversion reaction to the purchased compound (AM, other peptides, etc.) based on the above-mentioned literature, and a method of applying an appropriate conversion reaction.
  • a method of preparing by oneself can be exemplified.
  • the AM derivatives disclosed in the above literature can sustainably exhibit the pharmacological effects of adrenomedullin without substantially causing undesired serious side effects. Therefore, in each aspect of the present invention, by using the AM derivative disclosed in the above document as an active ingredient, the adrenomedulin activity of the AM derivative can be substantially avoided while substantially avoiding the occurrence of undesired serious side effects. , Especially through antiviral activity, can prevent or treat the symptoms or disorders of viral infections in subjects with viral infections, such as human patients with viral infections.
  • adrenomedullin or its derivative is described below: (I) A peptide consisting of the amino acid sequence of adrenomedulin, (Ii) A peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine residues in the amino acid sequence form a disulfide bond. (Iii) In the peptide of (ii), the peptide in which the disulfide bond is substituted with an ethylene group, (Iv) A peptide in which 1 to 15 amino acid residues are deleted, substituted or added in any of the peptides of (i) to (iii).
  • the adrenomedullin or its derivative is described below: (I) A peptide consisting of the amino acid sequence of adrenomedulin, (Ii) A peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine residues in the amino acid sequence form a disulfide bond. (V) In the peptide of (i) or (ii), the peptide in which the C-terminal is amidated, (Vi) In the peptide of (i) or (ii), the peptide having a glycine residue added to the C-terminal, and any of (vii) (i), (ii), (v) and (vi).
  • a modifying group containing a C 4 -C 30 alkyl group, a C 4 -C 30 alkenyl group or a polyethylene glycol group at the N-terminal ⁇ -amino group of the peptide, the Fc region of immunoglobulin, and serum albumin Selected from the group consisting of a modifying group containing a C 4 -C 30 alkyl group, a C 4 -C 30 alkenyl group or a polyethylene glycol group at the N-terminal ⁇ -amino group of the peptide, the Fc region of immunoglobulin, and serum albumin.
  • Peptides in which organic groups are attached with or without linking groups It is more preferable that the peptide or compound is selected from the group consisting of.
  • the peptide consists of the amino acid sequence of adrenomedulin contained in (v), the C-terminal is amidated, and the two cysteine residues in the amino acid sequence are disulfides.
  • the peptide forming the bond corresponds to the mature native adrenomedulin.
  • the peptide consisting of the amino acid sequence of (i) adrenomedulin corresponds to the pre-translational (ie immature) form of natural adrenomedulin that has undergone post-translational modification of C-terminal amidation and disulfide of cysteine residues.
  • the peptide (ii) is formed by air-oxidizing the thiol groups of the two cysteine residues of the peptide (i) or by oxidizing them with an appropriate oxidizing agent to convert them into disulfide bonds. Can be made to.
  • the three-dimensional structure of the peptide can be made to resemble the three-dimensional structure of natural adrenomedullin.
  • the adrenomedullin activity of the peptide of (ii) can be made substantially equivalent to that of the natural adrenomedullin.
  • the peptide of (iii) can be formed by converting the disulfide bond of the peptide of (ii) into an ethylene group. Substitution of disulfide bonds to ethylene groups can be performed by methods well known in the art (O. Keller et al., Helv. Chim. Acta, 1974, Vol. 57, p. 1253). By using the peptide of (iii) above, the three-dimensional structure of the peptide can be stabilized. As a result, the peptide of (iii) can continuously express adrenomedulin activity in vivo.
  • the amino acid residues deleted, substituted or added in the peptide of (iv) are, for example, in the range of 1 to 15, in the range of 1 to 10, and in the range of 1 to 8. It is in the range of 1 to 5 or 1 to 3.
  • the peptide of (iv) is the peptide of any of (i) to (iii) at positions 1-15, 1-12, 1-10, 1-8, from the N-terminal side. It is an N-terminal deleted peptide in which amino acid residues at positions 1 to 5 or 1 to 3 are deleted.
  • the peptide of (iv) is the peptide of any of (i) to (iii) at positions 1-15, 1-14, 1-13, 1-12, from the N-terminal side.
  • N-terminal deletion peptides in which amino acid residues at positions 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6 or 1 to 5 are deleted. be.
  • one or more amino acid residues (for example, 1 to 5, 1 to 3, or 1 or 2) may be further deleted, substituted or added.
  • the adrenomedullin activity of the peptide can be made substantially equivalent to that of the natural adrenomedullin.
  • the peptide can continuously express adrenomedulin activity in vivo.
  • the N-terminal deleted peptide in (iv) has the amino acid residues 1 to 12 deleted from the N-terminal side in any of the peptides (i) to (iii). It can be a peptide (hereinafter, may be referred to as "AM (13-52)"), and further, a peptide in which 1 to 3 amino acid residues are substituted or deleted.
  • AM (13-52) SFGCRFGTCTVQKLAHQIYQF-TDKDKDNVAPRSKISPQGY (SEQ ID NO: 14)
  • the disulfide bond of the peptide (ii) is between the cysteine residue at position 4 and the cysteine residue at position 9 in the amino acid sequence of SEQ ID NO: 14.
  • the 1 to 3 amino acid residues to be further substituted or deleted are not the cysteine residues at positions 4 and 9 in the amino acid sequence of SEQ ID NO: 14, but any one of the amino acid residues at positions 29 to 35. ⁇ 3 pieces.
  • the peptide (iv) can be, for example, a peptide in which the amino acid residue at position 32 or 33 in the amino acid sequence of SEQ ID NO: 14 is substituted.
  • the peptide (iv) can be a peptide in which the amino acid residue at position 32 in the amino acid sequence of SEQ ID NO: 14 is substituted.
  • the peptide (iv) can be a peptide consisting of any of the amino acid sequences of SEQ ID NOs: 15-22. In certain embodiments, the peptide (iv) can be a peptide consisting of the amino acid sequence of SEQ ID NO: 17.
  • the adrenomedulin or a derivative thereof consists of the amino acid sequence of any of SEQ ID NOs: 15 to 22, the C-terminus is amidated, and the cysteine residue at the 4-position and the cysteine residue at the 9-position are present.
  • a peptide forming a disulfide bond for example, consisting of the amino acid sequence of SEQ ID NO: 17, the C-terminal is amidated, and the cysteine residue at the 4-position and the cysteine residue at the 9-position form a disulfide bond.
  • the adrenomedullin or a derivative thereof of the present embodiment is remarkable in terms of, for example, biological stability as compared with AM while maintaining substantially the same pharmacological action as the parent compound AM.
  • the peptide of (vi) can be converted into the peptide of (v) by converting the C-terminal glycine residue into a C-terminal amide group by the action of the C-terminal amidating enzyme. Therefore, by administering the peptide (vi) to a subject, a C-terminal amidated peptide can be formed in the living body of the subject after a lapse of a certain period of time. As a result, the peptide (vi) can continuously express adrenomedulin activity in vivo.
  • the compound of (vii) can have remarkably excellent pharmacokinetics, for example, with respect to biological stability, while maintaining the adrenomedullin activity of the peptides of (i) to (vi).
  • B A peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4 and in which the cysteine residue at position 16 and the cysteine residue at position 21 form a disulfide bond
  • C A peptide consisting of the amino acid sequence of SEQ ID NO: 6 or a peptide consisting of the amino acid sequence of SEQ ID NO: 6 in which the cysteine residue at position 16 and the cysteine residue at position 21 form a disulfide bond
  • D A peptide consisting of the amino acid sequence of SEQ ID NO: 8 or a peptide consisting of
  • a modifying group selected from the group consisting of a C 4 -C 30 alkyl group, a C 4 -C 30 alkenyl group, a modifying group containing a polyethylene glycol group, an immunoglobulin Fc region, and a serum albumin is added to the ⁇ -amino group as a linking group.
  • the adrenomedullin or its derivative is described below: (A) A peptide consisting of the amino acid sequence of SEQ ID NO: 1 or a peptide consisting of the amino acid sequence of SEQ ID NO: 1 and in which the cysteine residue at position 16 and the cysteine residue at position 21 form a disulfide bond; (B) A peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4 and in which the cysteine residue at position 16 and the cysteine residue at position 21 form a disulfide bond; (C) A peptide consisting of the amino acid sequence of SEQ ID NO: 6 or a peptide consisting of the amino acid sequence of SEQ ID NO: 6 in which the cysteine residue at position 16 and the cysteine residue at position 21 form a disulfide bond; (D) A peptide consisting of the amino acid sequence of SEQ ID NO: 8 or a peptid
  • the number of amino acid residues deleted, substituted or added is preferably in the range of 1 to 12, more preferably in the range of 1 to 10, and is preferably in the range of 1 to 8.
  • the range of 1 is more preferable, the range of 1 to 5 is particularly preferable, and the range of 1 to 3 is most preferable.
  • Suitable peptides (h) are 1 to 15 positions, 1 to 12 positions, 1 to 10 positions, 1 to 8 positions, and 1 to 5 positions from the N-terminal side in any of the peptides (a) to (g). It is a peptide in which the amino acid residue at the position or the 1st to 3rd position is deleted.
  • the amino acid residues at positions 1 to 15, 1 to 10 or 1 to 5 are deleted from the N-terminal side in any of the peptides (a) to (d). Or, in the peptide of (e) or (f), the amino acid residue at the 1st to 13th position, the 1st to 8th position, or the 1st to 5th position is deleted from the N-terminal side. In the preferred peptide, one or more (eg, 1-5, 1-3, or 1 or 2) amino acid residues may be further deleted, substituted or added.
  • the adrenomedullin activity of the peptide can be made substantially equivalent to that of the natural adrenomedullin.
  • the peptide can continuously express adrenomedulin activity in vivo.
  • AM or a derivative thereof used as an active ingredient includes not only the compound itself but also a salt thereof.
  • AM or a derivative thereof is in the form of a salt, it is preferably a pharmaceutically acceptable salt.
  • the counter ion of the salt of AM or a derivative thereof is not limited, but is, for example, a cation such as a sodium ion, a potassium ion, a calcium ion, a magnesium ion, or a substituted or unsubstituted ammonium ion, or a chloride ion.
  • AM or a derivative thereof used as an active ingredient includes not only the compound itself but also a solvate of the compound or a salt thereof.
  • AM or a derivative thereof, or a salt thereof is in the form of a solvate, it is preferably a pharmaceutically acceptable solvate.
  • the solvent that can form a solvent with the compound or a salt thereof is not limited, and is, for example, water, or methanol, ethanol, 2-propanol (isopropyl alcohol), dimethyl sulfoxide (DMSO), acetic acid, ethanol.
  • Organic solvents such as amine, acetonitrile or ethyl acetate are preferred.
  • the adrenomedullin activity of the compound can be substantially equivalent to that of the natural adrenomedullin.
  • AM or its derivatives used as an active ingredient also includes individual enantiomers and diastereomers of the compound, as well as mixtures of stereoisomers of the compound, such as racemates. ..
  • AM or a derivative thereof can exhibit antiviral effects such as virus growth suppression, inactivation and / or killing.
  • AM or a derivative thereof maintains the pharmacological action of the natural adrenomedulin, and through the antiviral action, the symptom of the viral infection in a subject having a viral infection, for example, a human patient having the viral infection. Or the disorder can be prevented or treated.
  • AM or its derivatives can exhibit antiviral effects such as viral growth inhibition, inactivation and / or killing. Therefore, another aspect of the present invention relates to a pharmaceutical agent containing adrenomedullin or a derivative thereof as an active ingredient for preventing or treating a symptom or disorder in a subject having a viral infection.
  • the pharmaceutical of this embodiment can prevent or treat symptoms or disorders in a subject having a viral infection through antiviral effects such as viral growth inhibition, inactivation and / or death.
  • AM or a derivative thereof used as an active ingredient may be used alone or in combination with one or more pharmaceutically acceptable ingredients.
  • the antiviral agent and the pharmaceutical of this embodiment can be formulated into various dosage forms commonly used in the art, depending on the desired administration method. Therefore, the antiviral agent and the pharmaceutical of this embodiment can also be provided in the form of a pharmaceutical composition containing adrenomedulin or a derivative thereof and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is, in addition to the above-mentioned components, one or more pharmaceutically acceptable media (for example, a solvent such as sterile water or a solution such as physiological saline), an excipient.
  • Excipients such as painkillers, antioxidants, sweeteners and flavoring agents may be included.
  • the dosage form of the antiviral agent and the pharmaceutical of this embodiment is not particularly limited and may be a preparation for use in parenteral administration, and may be a transmucosa (for example, transnasal, sublingual or oral cavity mucosa, etc.). It may be a preparation for use in transdermal, transanal (enema), or transvaginal administration, or it may be a preparation for use in oral administration.
  • the dosage form of the antiviral agent and the pharmaceutical agent of this embodiment may be a unit-dose form or a plurality of dosage forms.
  • Formulations for use in parenteral administration include, for example, injections such as sterile solutions or suspensions with water or other pharmaceutically acceptable liquids.
  • Additives that can be mixed with the injection are, but are not limited to, isotonic containing, for example, physiological saline, glucose or other adjuvants (eg, D-sorbitol, D-mannitol or sodium chloride).
  • Vehicles such as liquids, solubilizers such as alcohols (eg ethanol or benzyl alcohol), esters (eg benzyl benzoate), polyalcohols (eg propylene glycol or polyethylene glycol), polysorbate 80 or polyoxyethylene hydrogenated castor oil.
  • Nonionic surfactants such as oily liquids such as sesame oil or soybean oil, buffers such as phosphate buffers or sodium acetate buffers, soothing agents such as benzalconium chloride or prokine hydrochloride, humans.
  • Stabilizers such as serum albumin or polyethylene glycol, preservatives, antioxidants and the like can be mentioned.
  • the prepared injection is usually filled in a suitable container (eg, vial or ampoule) and stored in a suitable environment until use.
  • the antiviral agent and the drug of this embodiment can also be used in combination with one or more other drugs useful as a drug.
  • the antiviral agent and the pharmaceutical product of this embodiment may be provided in the form of a single pharmaceutical product containing AM or a derivative thereof and one or more other agents, and may be provided with AM or a derivative thereof and one or more kinds. It may be provided in the form of a pharmaceutical combination or kit containing a plurality of formulations formulated separately from other agents. In the case of a pharmaceutical combination or in the form of a kit, the respective formulations can be administered simultaneously or separately (eg, sequentially).
  • AM or its derivatives When AM or its derivatives are applied for pharmaceutical use, AM or its derivatives include not only the compound itself, but also pharmaceutically acceptable salts of the compound and solvates thereof which are pharmaceutically acceptable.
  • the pharmaceutically acceptable salt of AM or its derivative and the pharmaceutically acceptable solvate thereof are not limited, but for example, the salt or solvate exemplified above is preferable.
  • the compound When AM or a derivative thereof is in the form of the salt or solvate, the compound can be applied to the desired pharmaceutical use.
  • AM or its derivative When AM or its derivative is applied to pharmaceutical use, AM or its derivative includes not only the compound itself but also the prodrug form of the compound.
  • prodrug means a compound that is converted to a parent drug in vivo.
  • the prodrug form of AM or its derivatives is, but is not limited to, for example, an ester of a hydroxyl group of AM or its derivative with an arbitrary carboxylic acid, an amide of the hydroxyl group with any amine, and AM or Examples thereof include an amide of the amino group of the derivative and an arbitrary carboxylic acid.
  • the pharmaceutical of this embodiment like the antiviral agent of one aspect of the present invention described above, has a subject having a viral infection, such as a viral infection, through the antiviral action of AM or a derivative thereof. It can be used to prevent or treat the symptoms or disorders of viral infections in human patients.
  • the viral infection is, for example, viral pneumonia, viral myocarditis, viral encephalitis, viral hemorrhagic fever, viral nephropathy, viral gastroenteritis, viral vasculitis, viral stomatitis. , Viral keratitis or viral neuritis.
  • the medicine of this embodiment when the medicine of this embodiment is applied to a subject having viral pneumonia, for example, a human patient having viral pneumonia, the medicine of this embodiment is an organ disorder, a respiratory disorder (for example,) in the subject or a human patient.
  • a respiratory disorder for example,
  • the medicine of this embodiment is an organ disorder, a respiratory disorder (for example,) in the subject or a human patient.
  • a respiratory disorder for example, in the subject or a human patient.
  • multi-organ failure eg, lung, kidney, liver, heart, blood vessel or cerebral nerve organ failure
  • the agent of this embodiment when the agent of this embodiment is applied to a subject having viral myocarditis, eg, a human patient with viral myocarditis, the agent of this embodiment prevents myocarditis in the subject or human patient. Or preferably used for treatment.
  • the medicine of this embodiment when the medicine of this embodiment is applied to a subject having viral encephalitis, for example, a human patient having viral encephalitis, the medicine of this embodiment prevents or treats encephalitis in the subject or human patient. It is preferable to use it for.
  • the medicine of this embodiment when the medicine of this embodiment is applied to a subject having viral hemorrhagic fever, for example, a human patient having viral hemorrhagic fever, the medicine of this embodiment prevents hemorrhagic fever in the subject or human patient. Or preferably used for treatment.
  • a subject of this embodiment when a subject of this embodiment is applied to a subject having viral nephropathy, eg, a human patient with viral nephropathy, the medication of this embodiment prevents nephropathy in the subject or human patient. Or preferably used for treatment.
  • the agent of this embodiment when the agent of this embodiment is applied to a subject having viral gastroenteritis, eg, a human patient having viral gastroenteritis, the agent of this embodiment prevents gastroenteritis in the subject or human patient. Or preferably used for treatment.
  • the agent of this embodiment when the agent of this embodiment is applied to a subject having viral vasculitis, eg, a human patient with viral vasculitis, the agent of this embodiment prevents vasculitis in the subject or human patient. Or preferably used for treatment.
  • the agent of this embodiment when the agent of this embodiment is applied to a subject having viral stomatitis, eg, a human patient having viral stomatitis, the agent of this embodiment prevents or treats stomatitis in the subject or human patient.
  • the agent of this embodiment when the agent of this embodiment is applied to a subject having viral keratitis, eg, a human patient with viral keratitis, the agent of this embodiment prevents keratitis in the subject or human patient. Or preferably used for treatment.
  • the agent of this embodiment when the agent of this embodiment is applied to a subject having viral neuritis, eg, a human patient with viral neuritis, the agent of this embodiment prevents neuritis in the subject or human patient. Or preferably used for treatment.
  • the pharmaceutical of this embodiment for the prevention or treatment of the symptoms or disorders of the viral infections exemplified above in a subject having a viral infection, eg, a human patient with a viral infection, of AM or a derivative thereof.
  • a subject having a viral infection eg, a human patient with a viral infection, of AM or a derivative thereof.
  • the symptoms or disorders of the viral infection can be prevented or treated.
  • AM or its derivative used as the active ingredient of the antiviral agent and the drug of this embodiment is derived from adrenomedullin, which is a natural bioactive peptide.
  • pharmaceuticals containing AM or its derivatives as active ingredients are being clinically tested as therapeutic agents for various diseases and the like. For this reason, AM or its derivatives have been established to be safe and low toxicity. Therefore, the antiviral agents and pharmaceuticals of this embodiment can be applied to various subjects in need of prevention or treatment of symptoms or disorders of viral infections.
  • the subject is a subject or patient of a human or non-human mammal (eg, a warm-blooded animal such as a pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, hamadryas baboon or chimpanzee). It is preferably present, and more preferably a human patient.
  • a human or non-human mammal eg, a warm-blooded animal such as a pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, hamadryas baboon or chimpanzee.
  • the exact dosage and administration will be the exact condition of the subject's age, gender, symptoms, diseases and / or disorders to be prevented or treated.
  • the physician in charge should ultimately determine the therapeutically effective dosage and administration in light of many factors (eg, severity) and the route of administration. Therefore, in the antiviral agent and the pharmaceutical of this embodiment, AM or a derivative thereof, which is an active ingredient, is administered to a subject in a therapeutically effective dosage and administration (for example, dose and route of administration).
  • the antiviral agent and the drug of this embodiment are administered to a target, particularly a human patient, AM or a derivative thereof used as an active ingredient, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.
  • the dose of the solvate is usually in the range of 0.01 to 1000 ⁇ g / kg body weight / day, for example in the range of 0.5 to 200 ⁇ g / kg body weight / day.
  • the antiviral agent and the drug of this embodiment may be administered by any administration route.
  • the antiviral agent and the drug of this embodiment are preferably administered by a route such as intravenous administration, enema administration, subcutaneous administration, intramuscular administration, oral administration or intraperitoneal administration, and may be administered intravenously. It is more preferable, and it is further preferable to administer it intravenously continuously.
  • AM or its derivatives are viral infections in subjects with viral infections, such as human patients with viral infections, through antiviral effects such as viral growth suppression, inactivation and / or death. It can be used to prevent or treat the symptoms or disorders of the virus. Therefore, another aspect of the present invention relates to a prophylactic or therapeutic agent for a viral infection, which comprises AM or a derivative thereof as an active ingredient.
  • the prophylactic or therapeutic agent of this aspect has the same characteristics as the antiviral agent and pharmaceutical of this aspect described above.
  • the prophylactic or therapeutic agent of this embodiment can be used in the same dosage and administration as the antiviral agent and pharmaceutical of this embodiment described above.
  • the prophylactic or therapeutic agent of this embodiment prevents or impairs the symptoms or disorders of a viral infection in a subject having a viral infection, eg, a human patient with a viral infection, through the antiviral action of AM or a derivative thereof.
  • a viral infection is, for example, viral pneumonia, viral myocarditis, viral encephalitis, viral hemorrhagic fever, viral nephropathy, viral gastroenteritis, viral vasculitis, Viral stomatitis, viral keratitis or viral neuritis.
  • the symptoms or disorders of a viral infection are, for example, in the case of viral pneumonia, organ disorders, respiratory disorders (eg, cough or respiratory distress, etc.), fever, muscle pain, general malaise. , Hemorrhagic, hemorrhagic shock, or multi-organ failure (eg, lung, kidney, liver, heart, blood vessel or cerebral nerve organ failure), especially organ damage; in the case of viral myocarditis, myocarditis; In the case of viral encephalitis, it is encephalitis; in the case of viral hemorrhagic fever, it is hemorrhagic fever; in the case of viral nephropathy, it is nephropathy; in the case of viral gastroenteritis, it is gastroenteritis; In the case of vasculitis; in the case of viral stomatitis, it is stomatitis; in the case of viral keratitis, it is keratitis; and in the case of viral neuriti
  • Another aspect of the invention is an effective amount of AM or a derivative thereof, or a pharmaceutically acceptable salt thereof, or pharmaceuticals thereof, for a subject having a viral infection, for example, a human patient having a viral infection.
  • Prevention of symptoms or disorders of the viral infection including administration of an acceptable hydrate to exert antiviral effects on the virus such as growth inhibition, inactivation and / or death. Or it is a treatment method.
  • the AM or its derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate thereof administered in the method of this embodiment is the active ingredient of the antiviral agent and the pharmaceutical of the present embodiment described above. Has the same characteristics as.
  • the method of this embodiment can be carried out at the same dosage and administration as the antiviral agent and drug of this embodiment described above.
  • the viral infection is, for example, viral pneumonia, viral myocarditis, viral encephalitis, viral hemorrhagic fever, viral nephropathy, viral gastroenteritis, viral vasculitis, viral stomatitis. , Viral keratitis or viral neuritis.
  • the symptom or disorder of the viral infection is, for example, in the case of viral pneumonia, organ disorder, respiratory disorder (eg cough or respiratory difficulty, etc.), fever, muscle pain, general malaise, septicemia, etc.
  • Hemorrhagic shock or multi-organ failure (eg, lung, kidney, liver, heart, blood vessel or cerebral nerve organ failure), especially organ damage; in the case of viral myocarditis, myocarditis; viral encephalitis If it is encephalitis; if it is viral hemorrhagic fever, it is hemorrhagic fever; if it is viral nephropathy, it is nephropathy; if it is viral gastroenteritis, it is gastroenteritis; It is vasculitis; in the case of viral stomatitis, it is stomatitis; in the case of viral keratitis, it is keratitis; and in the case of viral neuritis, it is neuritis.
  • a subject having a viral infection for example, a human patient having a viral infection
  • the symptoms or disorders of the viral infection exemplified above via antiviral action. can be prevented or treated.
  • Another aspect of the invention is in a subject with a viral infection, eg, a human patient with a viral infection, through antiviral effects such as growth suppression, inactivation and / or death against the virus.
  • Yet another aspect of the invention is mediated by antiviral effects such as growth suppression, inactivation and / or death against the virus in a subject having a viral infection, eg, a human patient with a viral infection.
  • viral infections include, for example, viral pneumonia, viral myocarditis, viral encephalitis, viral hemorrhagic fever, viral nephropathy, viral gastroenteritis, viral vasculitis, Viral stomatitis, viral keratitis or viral neuritis.
  • viral infections include, for example, viral pneumonia, viral myocarditis, viral encephalitis, viral hemorrhagic fever, viral nephropathy, viral gastroenteritis, viral vasculitis, Viral stomatitis, viral keratitis or viral neuritis.
  • the symptoms or disorders of the viral infection are, for example, in the case of viral pneumonia, organ disorder, respiratory disorder (eg cough or respiratory difficulty, etc.), fever, muscle pain, general malaise. , Hemorrhagic, hemorrhagic shock, or multi-organ failure (eg, lung, kidney, liver, heart, blood vessel or cerebral nerve organ failure), especially organ damage; in the case of viral myocarditis, myocarditis; In the case of viral encephalitis, it is encephalitis; in the case of viral hemorrhagic fever, it is hemorrhagic fever; in the case of viral nephropathy, it is nephropathy; in the case of viral gastroenteritis, it is gastroenteritis; In the case of vasculitis; in the case of viral stomatitis, it is stomatitis; in the case of viral keratitis, it is keratitis; and in the case of viral neuritis, it is neuritis.
  • organ disorder
  • ⁇ Test I Antiviral effect of adrenomedullin against various viruses (1)> An in vitro plaque formation suppression test was conducted using AM to evaluate the antiviral effect of AM on various viruses.
  • A Active ingredient Synthetic human adrenomedulin (a peptide consisting of the amino acid sequence of SEQ ID NO: 1, the C-terminal is amidated, and the two cysteine residues in the amino acid sequence form a disulfide bond). Freeze-dried powder.
  • B Medium 3.75 w / v% Mannitol-0.5 w / v% Aqueous glycine solution.
  • C Preparation of administered sample To the vial containing the active ingredient, 1.4 mL of 5% mannitol solution was added to dissolve the active ingredient, and a high-concentration sample solution of 1000 ⁇ M was prepared.
  • This sample solution was dispensed in 100 ⁇ L increments and cryopreserved at -20 ° C.
  • the high-concentration sample solution was diluted 100-fold to prepare a medium-concentration sample solution of 10 ⁇ M.
  • the medium-concentration sample solution was diluted 100-fold to prepare a low-concentration sample solution of 100 nM.
  • MA-104 cells and Vero cells are 10% bovine fetal serum (FBS, GE Healthcare Life Sciences) -containing MEM medium (Sigma-Aldrich), MDCK cells and CRFK cells are 10% FBS-containing DMEM.
  • FBS bovine fetal serum
  • MEM medium Sigma-Aldrich
  • MDCK cells and CRFK cells are 10% FBS-containing DMEM.
  • IMDM medium containing 10% FBS SIGMA
  • HCT-8 cells RPMI1640 medium containing 10% FBS (Thermofisher Scientific) was used.
  • Each host cell was subcultured on the bottom surface of a 25 cm 2 culture flask according to a predetermined procedure so as to form a single-layer sheet. The medium was removed and the cells were washed twice with PBS.
  • Cells were detached by adding 1 mL of 0.05% trypsin to one 25 cm 2 culture flask.
  • the recovered solution containing the detached cells was transferred to a 15 mL centrifuge tube.
  • the recovered solution was mixed with an equal amount of fresh medium and centrifuged (1000 rpm, 190 ⁇ g, 24 ° C.) for 5 minutes to remove the supernatant.
  • 1 mL of fresh medium was added to the residue and resuspended. The entire amount of the resuspension was placed in a sterile medium bottle.
  • Fresh medium was added to this and seeded in 15 mL each in a 75 cm 2 culture flask or 2 mL each in a 6-well plate.
  • the seeded host cells were cultured in a carbon dioxide incubator (33 or 37 ° C., CO 2 concentration: 5%). It was confirmed that the host cells became a single-layer sheet on the bottom surface of a 75 cm 2 -culture flask or a 6-well plate.
  • C Preparation of inoculated virus solution
  • the cryopreserved virus strain was thawed and appropriately diluted with a fresh medium corresponding to the host cells. This diluted solution was added to a 75 cm 2 culture flask in which the host cells were cultured. The host cells were cultured in a carbon dioxide incubator for 1 hour (33 or 37 ° C., CO 2 concentration: 5%), and the virus was adsorbed on the host cells. Then, the virus diluent was removed. Fresh medium without trypsin or containing 2-3 ⁇ g / mL trypsin was added to the host cells and the host cells were cultured in a carbon dioxide incubator until a cytopathic effect (CPE) appeared.
  • CPE cytopathic effect
  • the supernatant containing the virus and the host cells were collected.
  • the collected supernatant was frozen and thawed three times. Then, it was centrifuged (2000 rpm, 780 ⁇ g, 4 ° C., 5 minutes), and the supernatant was obtained as an inoculum virus stock solution.
  • the obtained inoculated virus stock solution was dispensed into a serum tube in 1 mL increments and stored frozen (-80 ° C) until use.
  • the virus concentration was measured according to the prescribed procedure.
  • Rotavirus and influenza virus inoculated virus stock solutions were diluted with fresh MEM medium to a virus concentration of 400 PFU / mL.
  • the diluted solution was mixed with an equal amount of trypsin inhibitor to obtain an inoculated virus solution (200 PFU / mL).
  • the inoculated virus stock solution of herpesvirus, murine norovirus, feline calicivirus and coronavirus was diluted with MEM fresh medium to a virus concentration of 200 PFU / mL to obtain an inoculated virus solution (200 PFU / mL).
  • Fig. 1 shows the relationship between the concentration of AM added to various viruses and the number of plaques formed.
  • the horizontal axis is the added AM concentration (M)
  • the vertical axis is the number of plaques formed in each well.
  • AM suppressed plaque formation in a concentration-dependent manner against any of the virus strains.
  • AM showed a remarkable plaque formation inhibitory effect on coronavirus, herpesvirus and rotavirus.
  • the number of plaques in the control group without the test drug was 130 ⁇ 2.9 for influenza virus, 123 ⁇ 6.1 for coronavirus, and 128 ⁇ 4.9 for feline calicivirus.
  • norovirus it was 105 ⁇ 4.3
  • herpes virus it was 128 ⁇ 2.8
  • rotavirus it was 110 ⁇ 6.3.
  • ⁇ Test II Antiviral effect of adrenomedullin against various viruses (2)> An in vitro plaque formation suppression test was conducted using AM in the same procedure as in Test I, and the antiviral effect of AM on various viruses was evaluated.
  • Test drug The same active ingredient as in Test I (synthetic human adrenomedulin (consisting of the amino acid sequence of SEQ ID NO: 1, the C-terminus is amidated, and the two cysteine residues in the amino acid sequence form a disulfide bond).
  • a lyophilized powder of peptide)) and a medium (3.75 w / v% mannitol-0.5 w / v% glycine aqueous solution) were used to prepare a sample to be administered by the same procedure.
  • Plaque formation suppression test A plaque formation inhibition test was performed in the same procedure as in Test I. For each test group (Table 2), the number of plaques was measured and the mean and standard error were calculated. Table 3 shows the results of the plaque formation suppression test.
  • AM suppressed plaque formation in a concentration-dependent manner against any of the virus strains.
  • AM showed a remarkable plaque formation inhibitory effect on coronavirus. From the above results, it was clarified that AM has antiviral activity against influenza virus and coronavirus, particularly coronavirus.
  • ⁇ Test III Organ protective effect of adrenomedullin on influenza virus-infected mice (1)> A drug efficacy test was conducted on influenza virus-infected mice using AM, and the effect of AM on organ damage in influenza virus-infected mice was evaluated.
  • [III-1: Test drug] Active ingredient Synthetic human adrenomedulin (a peptide consisting of the amino acid sequence of SEQ ID NO: 1, the C-terminal is amidated, and the two cysteine residues in the amino acid sequence form a disulfide bond). Freeze-dried powder.
  • B Medium 3.75 w / v% Mannitol-0.5 w / v% Aqueous glycine solution.
  • C Preparation of the drug to be administered To the vial containing the active ingredient, 1.4 mL of the medium was added to dissolve the active ingredient, and a 1000 ⁇ M sample solution was prepared.
  • This sample solution was dispensed in 100 ⁇ L increments and cryopreserved at -20 ° C.
  • This sample solution was diluted with a medium to prepare a sample solution of 0.5 nmol / kg / hour (low concentration) or 5 nmol / kg / hour (high concentration).
  • 100 ⁇ L of the sample solution was immediately filled in an osmotic pump (ALZET Osmotic Pump: 1007D). The weight of the pump before and after filling was measured to confirm that the sample solution was properly filled.
  • the sample solution was prepared at the time of use.
  • Influenza virus PR8 (A / PR / 8/34 (H1N1)), which is a preserved strain of the Department of Infection and Immunology, Aichi Medical University School of Medicine, was used as the virus strain and its host cell test. ..
  • (B) Preparation of inoculated virus solution The cryopreserved virus strain was thawed and appropriately diluted with fresh DMEM medium. This diluted solution was added to a culture flask in which MDCK cells, which are host cells, were cultured. The host cells were cultured in a carbon dioxide incubator for 1 hour (37 ° C., CO 2 concentration: 5%), and the virus was adsorbed on the host cells. Then, the virus diluent was removed. Fresh DMEM medium containing 0.25% trypsin was added to the host cells and the host cells were cultured in a carbon dioxide incubator until cytopathic effect (CPE) appeared. Then, the supernatant containing the virus and the host cells were collected.
  • CPE cytopathic effect
  • the collected supernatant was centrifuged (2000 rpm, 780 ⁇ g, 4 ° C., 5 minutes) to obtain the supernatant as an inoculum virus stock solution.
  • the obtained inoculated virus stock solution was dispensed into a serum tube in 1 mL increments and stored frozen (-80 ° C) until use.
  • the virus concentration was measured by a predetermined procedure using the inoculated virus stock solution.
  • the inoculated virus stock solution was diluted with fresh medium to a virus concentration of 2 ⁇ 10 6 PFU / mL to obtain an inoculated virus solution.
  • a low concentration (0.5 nmol / kg / hour) or high concentration (5 nmol / kg / hour) sample solution was subcutaneously administered at a flow rate of 0.5 ⁇ L / hour.
  • Mice in the AM-non-administered control group were subcutaneously dosed with the vehicle at the same flow rate.
  • Mice of each group were bred in a breeding room (controlled temperature: 18 to 28 ° C, controlled humidity: 30 to 80% RH, 12 hours each for light and dark).
  • Macroscopic examination of the lungs was performed separately for the left and right based on the evaluation methods shown in Table 5 below. Then, the left lung, right lung, kidney, liver and heart were removed and weighed with an electronic balance. The removed heart was crossed into three divisions. The central heart was preserved by immersing it in 10% neutral buffered formalin. The remaining upper and lower heart parts were placed in separate tubes and cryopreserved (-80 ° C). The removed kidneys were crossed into 3 divisions. The right kidney portion was cryopreserved (-80 ° C). The left kidney portion was preserved by immersing it in 10% neutral buffered formalin. The excised liver was vertically divided into two parts and further divided into three parts. One liver portion was cryopreserved (-80 ° C).
  • the remaining liver portion was stored by immersing it in 10% neutral buffered formalin.
  • a part of the left lung (about 10 to 20 mg) was cryopreserved (-80 ° C).
  • the remaining left lung area was stored by immersing it in 10% neutral buffered formalin.
  • the right lung was used for virological examination.
  • Table 6 shows the general condition scores of the mice in each group. The values in the table are the mean and standard error of the scores of the mice in each group.
  • Table 7 shows the weights of the mice in each group. The values in the table are the mean and standard error of the body weight of the mice in each group.
  • Table 8 shows the scores of gross lesion examination of lungs in each group.
  • the values in the table are the mean and standard error of the gross lung lesion test scores in each group of mice.
  • "*" indicates that there was a significant difference from the control group (*: p ⁇ 0.05).
  • Table 9 shows the virus concentration in the lungs of each group.
  • the values in the table are the mean and standard error of virus concentration ( ⁇ 10 4 PFU) in the right lung of each group of mice.
  • "*" and "**” indicate that there was a significant difference from the control group (*: p ⁇ 0.05, **: p ⁇ 0.01).
  • the formation of macroscopic lesions in the lung was significantly suppressed in the mice in the AM-administered group.
  • the virus concentration in the lung was significantly reduced in the mice in the AM-administered group.
  • ⁇ Test IV Organ protective effect of adrenomedullin on influenza virus-infected mice (2)> A drug efficacy test was conducted on influenza virus-infected mice using AM and AM analogs, and the effects of AM and AM analogs on organ damage in influenza virus-infected mice were evaluated.
  • Active ingredient 1 Synthetic human adrenomedulin (hAM (1-52)) (consisting of the amino acid sequence of SEQ ID NO: 1, the C-terminus is amidated, and the two cysteine residues in the amino acid sequence form a disulfide bond. Peptide) lyophilized powder.
  • Adrenomedulin analog [Ala-44] hAM (13-52) (consisting of the amino acid sequence of SEQ ID NO: 17, the C-terminal is amidated, and the two cysteine residues in the amino acid sequence are A lyophilized powder of a peptide that forms a disulfide bond).
  • mice in the control group not treated with AM were treated with the vehicle under the same conditions. Mice of each group were bred in a breeding room (controlled temperature: 18 to 28 ° C, controlled humidity: 30 to 80% RH, 12 hours each for light and dark). On the day of virus inoculation, 0.05 mL of the inoculated virus solution was dropped into the nasal cavity of each individual of the control group and the AM or AM relative-administered mice using a micropipette (1 ⁇ 10 5 PFU / mouse). .. The animals were bred until the 5th day after the inoculation, with the day after the inoculation as the 1st day after the inoculation. Over the breeding period, the same items as in Test III were evaluated by the same procedure.
  • Table 10 shows the general condition scores of the mice in each group. The values in the table are the mean and standard error of the scores of the mice in each group. In the table, "**" indicates that there was a significant difference from the control group (**: p ⁇ 0.01).
  • Table 11 shows the weights of the mice in each group. The values in the table are the mean and standard error of the body weight of the mice in each group.
  • Table 12 shows the scores of gross lesion examination of lungs in each group.
  • the values in the table are the mean and standard error of the gross lung lesion test scores in each group of mice.
  • "**" indicates that there was a significant difference from the control group (**: p ⁇ 0.01).
  • Table 13 shows the virus concentration in the lungs of each group.
  • the values in the table are the mean and standard error of virus concentration ( ⁇ 10 4 PFU) in the right lung of each group of mice.
  • "**" indicates that there was a significant difference from the control group (**: p ⁇ 0.01).
  • Table 14 shows the scores of histopathological examinations in the lungs of each group.
  • the values in the table are the mean and standard error of the scores of lung histopathology in each group of mice.
  • "**" indicates that there was a significant difference from the control group (**: p ⁇ 0.01).
  • the formation of macroscopic lesions in the lung was significantly suppressed in the mice in the hAM (1-52) -administered group and the [Ala-44] hAM (13-52) -administered group.
  • the virus concentration in the lung was significantly reduced in the mice in the hAM (1-52) -administered group and the [Ala-44] hAM (13-52) -administered group.
  • the present invention is not limited to the above-described embodiment, but includes various modifications.
  • the above-described embodiment has been described in detail in order to explain the present invention in an easy-to-understand manner, and is not necessarily limited to the one including all the configurations described.

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Abstract

La présente invention concerne un médicament présentant une activité antivirale contre divers virus capables d'induire des infections virales. Un aspect de la présente invention concerne un agent antiviral contenant de l'adrénomédulline ou un dérivé correspondant en tant que principe actif.
PCT/JP2021/032971 2020-09-09 2021-09-08 Agent antiviral WO2022054826A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009043481A2 (fr) * 2007-09-11 2009-04-09 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2015141819A1 (fr) * 2014-03-20 2015-09-24 国立大学法人宮崎大学 Dérivé d'adrénomédulline à action prolongée
WO2017047788A1 (fr) * 2015-09-18 2017-03-23 国立大学法人宮崎大学 Dérivé d'adrénomédulline à action prolongée

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009043481A2 (fr) * 2007-09-11 2009-04-09 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2015141819A1 (fr) * 2014-03-20 2015-09-24 国立大学法人宮崎大学 Dérivé d'adrénomédulline à action prolongée
WO2017047788A1 (fr) * 2015-09-18 2017-03-23 国立大学法人宮崎大学 Dérivé d'adrénomédulline à action prolongée

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KARAKAS MAHIR, JARCZAK DOMINIK, BECKER MARTIN, ROEDL KEVIN, ADDO MARYLYN M., HEIN FRAUKE, BERGMANN ANDREAS, ZIMMERMANN JENS, SIMON: "Targeting Endothelial Dysfunction in Eight Extreme-Critically Ill Patients with COVID-19 Using the Anti-Adrenomedullin Antibody Adrecizumab (HAM8101)", BIOMOLECULES, vol. 10, no. 8, 11 August 2020 (2020-08-11), pages 1171, XP055910417, DOI: 10.3390/biom10081171 *

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