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WO2018178935A1 - Pad2 destiné à l'utilisation dans la prévention et/ou le traitement ou le diagnostic d'infections causées par des virus de la famille des herpesviridae - Google Patents

Pad2 destiné à l'utilisation dans la prévention et/ou le traitement ou le diagnostic d'infections causées par des virus de la famille des herpesviridae Download PDF

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Publication number
WO2018178935A1
WO2018178935A1 PCT/IB2018/052204 IB2018052204W WO2018178935A1 WO 2018178935 A1 WO2018178935 A1 WO 2018178935A1 IB 2018052204 W IB2018052204 W IB 2018052204W WO 2018178935 A1 WO2018178935 A1 WO 2018178935A1
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WIPO (PCT)
Prior art keywords
pad2
viruses
amidine
herpesviridae family
inhibitor
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PCT/IB2018/052204
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English (en)
Inventor
Santo Landolfo
Francesca Gugliesi
Valentina DELL'OSTE
Sara PAUTASSO
Marco DE ANDREA
Gloria GRIFFANTE
Matteo BIOLATTI
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Universita' Degli Studi Di Torino
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Priority to EP18720365.8A priority Critical patent/EP3600386A1/fr
Publication of WO2018178935A1 publication Critical patent/WO2018178935A1/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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/50—Hydrolases (3) acting on carbon-nitrogen bonds, other than peptide bonds (3.5), e.g. asparaginase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]

Definitions

  • the present invention relates to PAD2 (peptidyl arginine deiminase, type 2) for use in preventing and/or treating or diagnosing infections caused by viruses of the Herpesviridae family.
  • PAD2 peptidyl arginine deiminase, type 2
  • Herpesviruses are double-stranded DNA icosahedral viruses belonging to the Herpesviridae family. Various Herpesviruses are responsible for infections, which can even be severe, in human beings. Eight human Herpesviruses are currently known: Herpes Simplex Virus type 1 (HSV-1), Herpes Simplex Virus type 2 (HSV-2), Varicella-Zoster Virus (VZV) , Cytomegalovirus (CMV) , Human Herpesvirus type 6, Human Herpesvirus type 7, Epstein-Barr Virus (EBV) , Human Herpesvirus type 8 (or Kaposi's sarcoma-associated herpesvirus, KSHV) .
  • HSV-1 Herpes Simplex Virus type 1
  • HSV-2 Herpes Simplex Virus type 2
  • VZV Varicella-Zoster Virus
  • CMV Cytomegalovirus
  • ESV Epstein-Barr Virus
  • KSHV Kaposi'
  • the elected antiviral drugs for herpes infections envisage the use of nucleoside analogues (e.g. ganciclovir) .
  • Nucleoside analogues can however have high toxicity for the host.
  • the use of ganciclovir or similar nucleoside derivatives in children (congenital infections or bone marrow transplant) due to the high myelotoxicity can have severe side effects which significantly limit their use .
  • nucleoside analogues frequently induce the appearance of resistance-associated mutations to the genes that code for viral enzymes (e.g. UL54 or UL97 of HCMV) used for the synthesis of DNA itself.
  • viral enzymes e.g. UL54 or UL97 of HCMV
  • a need is therefore felt to provide new targets for preventing and/or treating or diagnosing infections caused by viruses of the Herpesviridae family.
  • the object of the present invention is to provide a protein of the host cell involved in the viral replication of viruses of the Herpesviridae family, whose activity can be modulated so as to inhibit viral replication.
  • PAD2 peptidyl arginine deiminase, type 2
  • Inhibitors, antagonists and related compositions for use as antiviral agents against viruses of the Herpesviridae family are also provided .
  • FIG. 2 represents a graph of the mRNA expression levels of the enzymes of the PAD family in cells infected or not (mock) by HCMV;
  • FIG. 3A represents a graph of the enzyme activity of PAD2 in cells infected or not (mock) by HCMV;
  • FIG. 3B represents a graph of the measurement of the activity of scalar concentrations of the recombinant enzyme PAD2 (OD, optical density) ;
  • the PAD2 peptidyl arginine deiminase, type 2 protein is used in preventing and/or treating or in diagnosing infections caused by viruses of the Herpesviridae family.
  • PADs peptidyl arginine deiminases
  • PADs are a family of cellular enzymes that catalyse the citrullination reaction that consists of the deimination of arginine to citrulline.
  • the family of human and murine PADs is composed of five members, PAD 1-4 and PAD 6 that have peculiar tissue expression characteristics and substrate specificities.
  • PAD2 is expressed in different cell districts, such as muscle, brain, mammary glands, PAD4 mainly in hematopoietic cells such as neutrophils, monocytes and macrophages, PAD1 in the epidermis and the uterus, PAD3 in the pilifer follicles and PAD 6 at the ovules (Darrah et al . 2012; Wang and Wang 2013) .
  • An aberrant activation of the citrullination process can lead to the onset of antibodies against the citrullinated proteins as can be observed during the course of various inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, neoplasia and degenerative diseases (Bicker et al.2013; Nguyen H et al . 2016) .
  • antibodies appear against the citrullinated proteins, as well as a high deposit of immune complexes especially affecting the renal apparatus and the joints with severely compromised function of the organ.
  • the sequence of the PAD2 protein corresponds to the sequence SEQ ID NO: 2.
  • the nucleotide sequence of PAD2 corresponds to the sequence SEQ ID NO:l.
  • viruses of the Herpesviridae family are Cytomegalovirus, Herpes simplex Virus 1 or Herpes simplex Virus 2.
  • an inhibitor or antagonist of PAD2 is also used as an antiviral agent against viruses of the Herpesviridae family.
  • the inhibitor or antagonist is preferably selected from the group comprising Cl-amidine ( C16H20C I F3N4O4 , trifluoroacetate) , BB-Cl-amidine ( C26H26C IN5O ) , F-amidine ( C14H19 FN4O2 ⁇ C F3COOH , trifluoroacetate) , streptonigrin (C25H 2 2N 4 08) , YW3-56 ( C27H33C IN5O2 ) , TDFA ( Thr-Asp-F-amidine ) , TDCA ( Thr-Asp-Cl-amidine ) and derivatives thereof.
  • the inhibitor or antagonist is Cl-amidine.
  • the inhibitor or antagonist is preferably selected from the group comprising siRNA (short/small interfering RNA) specific for PAD2, miRNA (microRNA) specific for PAD2 and LNA (locked nucleic acid) specific for PAD2, dominant negative DNA specific for PAD2.
  • siRNA short/small interfering RNA
  • miRNA miRNA
  • LNA locked nucleic acid
  • the inhibitor or antagonist is a siRNA specific for PAD2.
  • a pharmaceutical composition comprising at least one inhibitor or antagonist of PAD2 and a pharmaceutical excipient is also used as an antiviral agent against viruses of the Herpesviridae family.
  • the pharmaceutical composition preferably comprises a further viral agent.
  • PAD2 is necessary for the replication of HCMV
  • the HIV virus a lentivirus, is not sensitive to the antiviral action of inhibitors of PAD2 ;
  • HCMV Cytomegalovirus
  • PAD2 is necessary for the replication of HCMV and that inhibitors of PAD2 inhibit the replication of Herpesviruses
  • PAD2 enzyme for preventing and/or treating infections caused by viruses of the Herpesviridae family .
  • HCMV cytomegalovirus
  • HFF Human Foreskin Fibroblasts
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS Fetal Bovine Serum
  • SIGMA-ALDRICH Fetal Bovine Serum
  • the cells were infected with HCMV, strain Merlin, at a multiplicity of infection (MOI) of 1 and collected at different times from the infection (24, 48, 72, 96 hours), or non-infected (mock) as a negative control.
  • the cells were lysed with a denaturing lysis buffer (1% SDS, 5 mM EDTA, SIGMA-ALDRICH) and subsequently quantified with the Lowry method (BIO-RAD Laboratories) .
  • the citrullination of the proteins was analysed through a technique based on the use of the rhodamine-phenylglyoxal probe (Rh-PG, CAYMAN CHEMICAL) which chemoselectively binds the citrulline in acidic pH conditions.
  • a reaction mixture was prepared containing: protein extract (10 ⁇ g) , 10 ⁇ tricarboxylic acid (20% final TCA, SIGMA-ALDRICH), Rh-PG (0.1 mM), PBS (SIGMA-ALDRICH), in a final volume of 30 ⁇ .
  • the samples were then incubated for an hour at 37 °C.
  • 3 ⁇ of Quenching solution (L-citrulline 100 mM, CAYMAN CHEMICAL) was added and the samples were incubated for 30 minutes in ice.
  • the samples were centrifuged at 13000 rpm for 15 minutes at 4°C and the protein pellet thus obtained was washed with 100% glacial acetone.
  • RNA level of transcription
  • HFF cells HFF cells
  • knock level of transcription
  • HCMV strain Merlin infected HFF cells
  • mock level of transcription-PCR - analysis was performed. The analysis was performed on mock cells or on cells infected with the HCMV virus at MOI 1, 24 hours from infection. The total RNA was extracted from the cells using the NucleoSpin RNA Kit (MACHEREY-NAGEL) . Subsequently 1 ⁇ iq of RNA was reverse transcribed using the Revert AidTM H Minus First Strand cDNA Synthesis Kit ( THERMO-FISHER SCIENTIFIC) .
  • THERMO-FISHER SCIENTIFIC Revert AidTM H Minus First Strand cDNA Synthesis Kit
  • the sample was placed at 25°C for 5 minutes then 42°C for 60 minutes and finally 70°C for 5 minutes in a PCR Reaction Buffer (250 mM Tris-HCl pH 8.3, 250 mM KC1, 200 mM MgC12, 500 mM DTT) mix containing 1 ⁇ random hexamer primer, 0.5 mM dNTP, 20 U/ ⁇ Ribolock RNase Inhibitor and 200 U/ ⁇ of RevertAid H Minus M-MuLV Reverse Transcritase in a final volume of 20 ⁇ .
  • PCR Reaction Buffer 250 mM Tris-HCl pH 8.3, 250 mM KC1, 200 mM MgC12, 500 mM DTT
  • TCCTCCATACCTCCAAGGAA (SEQ ID NO:12)); GAPDH: Fw 5'- AGTGGGTGTCGCTGTTGAAGT-3 ' (SEQ ID NO:13); Rw 5'- AACGTGTCAGTGGTGGACCTG-3 ' (SEQ ID NO:14)) .
  • each bar represents the expression value of each PAD normalised on GADPH (ACt) .
  • the results obtained from the RT-qPCR analysis demonstrate how, in human fibroblasts, the two most frequently expressed isoforms of the PAD family are PAD2 and PAD6.
  • Infection from HCMV causes an increase in the enzyme activity of the PAD2 enzyme.
  • an ELISA assay was prepared, based on the capacity of PAD2 to citrullinate the histone H3 substrate.
  • DMSO dimethyl sulfoxide
  • the cells were collected 15, 24, 48 and 72 hours after infection and lysed with a lysis buffer (100 mM Tris-HCl pH 7.5, 150 mM NaCl, 1% NP-40, 20 ⁇ 1/ ⁇ protease inhibitor cocktail -SIGMA) for 30 minutes in ice.
  • the samples were centrifuged subsequently for 30 min at 13000 rpm at 4°C to remove the cellular debris.
  • the proteins with molecular weight less than 30 kDa were removed through the use of concentrators (PierceTM Protein Concentrators PES, 30K MWCO, 0.5 mL) ; then, for every protein sample, 50 ⁇ g of extract, diluted 1:2 in a buffer for deimination without calcium (2 mM Dithiothreitol , 50 mM NaCl, 100 mM Tris-HCl pH 7.5), were incubated for about 20 hours at 37°C in a well where the histone H3 had been previously immobilized.
  • the results illustrated in Figure 3A show how there is a greater activation of the PAD2 enzyme in infected cells than in mock cells and, furthermore, that such activity is drastically reduced following treatment with the inhibitor Cl-amidine.
  • scalar concentrations of recombinant human PAD2 (from 10 to 2.5 mU) , diluted in an equal volume of lysis buffer of the samples and an equal volume of buffer for deimination with calcium (10 mM CaCl2, 2 mM dithiothreitol, 50 mM NaCl, 100 mM Tris-HCl pH 7.5), were incubated in the presence or absence of 100 ⁇ Cl- amidine or in the presence of the same volume of solvent, DMSO.
  • the PAD2 activity was calculated through an ELISA (Enzyme-Linked Immunosorbent Assay) , that analyses the capacity of the same enzymes to citrullinate the histone H3, known substrate of PAD2.
  • the absorbance value detected for each sample represents a measurement of the citrullinated histone H3 from which the blank was taken.
  • each point represents the value obtained from the untreated sample (triangle) , in the presence of Cl-amidine (circle) or DMSO (square), respectively.
  • the titration of the virus of the supernatants of the samples treated as previously described was performed 144 hours after infection through plaque assay. Specifically, the supernatant of the samples being examined and the cells were collected and lysed through three nitrogen/37 °C cycles and subsequently centrifuged at 1500 rpm for 10 min to remove the cellular debris.
  • HFF cells were cultivated in plates with 96 wells in 100 ⁇ of DMEM (SIGMA) with 10% of FBS, infected with serial dilutions of the virus and centrifuged at 2000 rpm for 30 minutes to promote the adsorption thereof. After 2 hours of incubation at 37°C 5% CO2 the viral inoculum was removed and replaced with 100 ⁇ of 0.8% methylcellulose (SIGMA), 1% FBS (SIGMA) .
  • Cl-amidine inhibits the replication of Herpes Simplex Virus type 1 and 2.

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Abstract

La présente invention concerne la PAD2 (peptidyle arginine désiminase, type (2)) pour l'utilisation dans la prévention et/ou le traitement ou le diagnostic d'infections causées par les virus de la famille des herpesviridae. La présente invention concerne également un inhibiteur ou un antagoniste de la PAD2 et des compositions pharmaceutiques apparentées pour l'utilisation comme agents antiviraux contre les virus de la famille des herpesviridae.
PCT/IB2018/052204 2017-03-29 2018-03-29 Pad2 destiné à l'utilisation dans la prévention et/ou le traitement ou le diagnostic d'infections causées par des virus de la famille des herpesviridae WO2018178935A1 (fr)

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EP18720365.8A EP3600386A1 (fr) 2017-03-29 2018-03-29 Pad2 destiné à l'utilisation dans la prévention et/ou le traitement ou le diagnostic d'infections causées par des virus de la famille des herpesviridae

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IT102017000034630A IT201700034630A1 (it) 2017-03-29 2017-03-29 Pad2 per uso nella prevenzione e/o trattamento o diagnosi di infezioni da virus della famiglia herpesviridae
IT102017000034630 2017-03-29

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112569338A (zh) * 2020-07-24 2021-03-30 上海谋始生物科技有限公司 Tdfa在制备预防和/或治疗眼表炎症疾病的药物中的应用
WO2024035035A1 (fr) * 2022-08-08 2024-02-15 재단법인 아산사회복지재단 Composition pour prévenir ou traiter une valvulopathie dégénérative comprenant un inhibiteur de pad
CN118001407A (zh) * 2024-04-02 2024-05-10 北京大学人民医院 Pad2在制备治疗缺血缺氧性恶性心律失常药物中的应用

Citations (2)

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WO2004046309A2 (fr) * 2002-11-18 2004-06-03 Phoenix Pharmacologics, Inc. Methodes d'inhibition d'une replication virale in vivo
WO2014086365A1 (fr) * 2012-12-03 2014-06-12 Rigshospitalet Anticorps anti-pad2 et traitement de maladies auto-immunes

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WO2004046309A2 (fr) * 2002-11-18 2004-06-03 Phoenix Pharmacologics, Inc. Methodes d'inhibition d'une replication virale in vivo
WO2014086365A1 (fr) * 2012-12-03 2014-06-12 Rigshospitalet Anticorps anti-pad2 et traitement de maladies auto-immunes

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GLORIA GRIFFANTE: "ESR9 - Citrullination during Human Cytomegalovirus infection: implications for autoimmune diseases", EDGE 2ND ANNUAL MEETING, 1 June 2018 (2018-06-01), http://edge-itn.eu/index.php/edge-phd?id=131, XP055481325 *
IZZO F ET AL: "Pegylated Arginine Deiminase Treatment of Patients with Unresectable Hepatocellular Carcinoma; Results from Phrase I/II Studies", JOURNAL OF CLINICAL ONCOLOGY, AMERICAN SOCIETY OF CLINICAL ONCOLOGY, US, vol. 22, no. 10, 1 May 2004 (2004-05-01), pages 1815 - 1822, XP002988856, ISSN: 0732-183X, DOI: 10.1200/JCO.2004.11.120 *
M. A. MOSCARELLO ET AL: "Inhibition of peptidyl-arginine deiminases reverses protein-hypercitrullination and disease in mouse models of multiple sclerosis", DISEASE MODELS & MECHANISMS, vol. 6, no. 2, 1 November 2012 (2012-11-01), GB, pages 467 - 478, XP055427970, ISSN: 1754-8403, DOI: 10.1242/dmm.010520 *
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112569338A (zh) * 2020-07-24 2021-03-30 上海谋始生物科技有限公司 Tdfa在制备预防和/或治疗眼表炎症疾病的药物中的应用
CN112569338B (zh) * 2020-07-24 2022-12-23 上海谋始生物科技有限公司 Tdfa在制备预防和/或治疗眼表炎症疾病的药物中的应用
WO2024035035A1 (fr) * 2022-08-08 2024-02-15 재단법인 아산사회복지재단 Composition pour prévenir ou traiter une valvulopathie dégénérative comprenant un inhibiteur de pad
CN118001407A (zh) * 2024-04-02 2024-05-10 北京大学人民医院 Pad2在制备治疗缺血缺氧性恶性心律失常药物中的应用

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