WO2008020085A2 - Utilisation de dérivés chlorométhylcétone et fluorométhylcétone dans des traitements antiviraux - Google Patents

Utilisation de dérivés chlorométhylcétone et fluorométhylcétone dans des traitements antiviraux Download PDF

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Publication number
WO2008020085A2
WO2008020085A2 PCT/EP2007/058628 EP2007058628W WO2008020085A2 WO 2008020085 A2 WO2008020085 A2 WO 2008020085A2 EP 2007058628 W EP2007058628 W EP 2007058628W WO 2008020085 A2 WO2008020085 A2 WO 2008020085A2
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sub
viral
hiv
inhibitors
infection
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PCT/EP2007/058628
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German (de)
English (en)
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WO2008020085A3 (fr
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Ulrich Schubert
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Virologik Gmbh
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Publication of WO2008020085A3 publication Critical patent/WO2008020085A3/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • 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
    • A61K38/55—Protease inhibitors
    • 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
    • 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 invention relates to agents for the treatment of acute and chronic infections with human and animal pathogenic viruses, which assemble on the cell membrane and are released by budding from the cell surface.
  • infectious diseases such as AIDS, hepatitis, haemorrhagic fever, SARS, smallpox, measles, polio or influenza.
  • the invention relates to agents containing as active ingredients inhibitors of protease and / or helicase activity. These include inhibitors of cellular protease, as well as substances that cause the unwinding of the DNA by influencing the ATP-dependent helicase. These agents interfere with the highly organized processes of virus replication and, consequently, the assembly of viral structural proteins.
  • virus proteins first assemble into virus-like particles in the cytosol of the cell or also the nucleus and later these virions are enveloped with processes of release from the cell membrane with a lipid membrane.
  • virus proteins that assemble on the cell membrane are usually released from the cell membrane by active budding. It comes to the formation of a virus bud (engl: bud), which actively everted from the cell membrane and then ultimately released by pinching off the cell surface in the form of a progeny virus.
  • HIV The principles of the late processes of virus replication will be presented using the example of HIV.
  • Main components of the HIV structural proteins are translated as three polyproteins: Gag and Gag-Pol for the inner core proteins and viral enzymes, and Env for the viral envelope proteins.
  • membrane targeting signals in the NH2-terminal domain of Gag are critical for transporting Gag to the cell membrane.
  • complete proteolytic processing of the Gag polyprotein Pr55 results in formation of the matrix (MA), capsid (CA), nucleocapsid (NC), and COOH-terminal p6 gag protein.
  • HIV virions are generally pinched off the plasma membrane as immature non-infectious virus particles; this process is called a virus budget.
  • proteolytic processing of gag and gag-pol polyproteins begins with activation of the viral protease (PR).
  • PR viral protease
  • Characteristic here is the condensation of the inner core, which results in the formation of a tapered core cylinder typical of the mature virus (summarized in Kösslich and Welker, 1996, Swanstrom and Wills, 1997).
  • the sequence underlying the inhibitor was determined by 2.2 A crystal structure analysis of human chymase (HC), a chymotrypsin-like serine protease expressed in mast cells (Pereira et al., 1999).
  • HC human chymase
  • a chymotrypsin-like serine protease expressed in mast cells Pereira et al., 1999.
  • the peptidyl-CMK inhibitor binds specifically and covalently to the amino acids Serl95 and His57 (Pereira et al., 1999).
  • VEIDFMK VPFCMK
  • LLFCMK LLFCMK
  • AAFCMK AAPYCMK
  • GGLCMK GGLCMK
  • the invention has for its object to provide means that are suitable for the treatment of acute and chronic infections with human and animal pathogenic viruses.
  • viruses are inherent in that they assemble in the cell, preferably on the cell membrane, and are released by budding from the cell surface.
  • pathogens of infectious diseases such as AIDS, hepatitis, haemorrhagic fever, SARS, smallpox, measles, polio, herpesvirus infections or influenza.
  • the invention relates to agents containing as active ingredients inhibitors of virus replication. These include inhibitors of cellular helicases as well as proteases that are provided with chemical protecting groups.
  • agents interfere with the highly organized processes of replication, assembly, and proteolytic maturation of viral structural proteins, thus preventing the release and production of infectious progeny viruses.
  • These agents have a broad spectrum of activity and can therefore be used as novel broad-spectrum antivirals for the prevention or therapy of different viral infections.
  • the object of the invention was achieved, inter alia, by the use of chemical inhibitors provided with inhibitors of serine proteases.
  • virus structural proteins are typically formed as precursor proteins in the form of polyproteins, which are then derived by the activity of proteases derived either from the host cell , but usually represent at least one virally encoded protease, are split into the so-called mature viral structure proteins.
  • This process is commonly referred to as virus maturation.
  • the ordered and finely tuned processes of assembly, maturation, budding and release are crucial for the successful generation of infectious progeny viruses.
  • the slightest disruption of these multi-layered processes can significantly disrupt the infectivity and / or the release of progeny viruses. All of these processes have one thing in common: they contain diverse and coordinated processes.
  • Fields of application are both the treatment and the prevention of viral infections.
  • There have been developed according to the invention means for the treatment of different viral infections, which are provided as effective inhibitors of protease and / or helicase activity with chemical protective groups.
  • the novel agents according to the invention are suitable for the treatment, therapy and inhibition of infections with different human pathogenic or animal-pathogenic viruses.
  • pathogens of chronic infectious diseases such as AIDS (HIV-1 and HIV-2), hepatitis (HCV and HBV), the causative agent of the Severe Acute Respiratory Syndrome (SARS), the SARS-CoV (Coronavirus ); poxviruses, viral haemorrhagic fever (VHF) pathogens, such as the Ebola virus as a member of the Filoviridae family; of influenza agents, such as the influenza A virus.
  • various anti-viral effects can be triggered in infected cells. These concern, for example, the inhibition of the replication of viral genetic information by influencing helicase activity.
  • a therapeutic effect can be effected by blocking viral replication in the organism.
  • the objects of the invention are achieved by the use of at least one inhibitor of helicase and / or protease activity, which is provided with chemical protecting groups.
  • agents for the treatment of viral infections containing as an effective component with chemical protecting groups inhibitors of transcription and / or protein processing in pharmaceutical preparations.
  • these inhibitors and substances are taken up by cells of higher eukaryotes and after cell uptake either indirectly block the activities of helicases of the host cells or in the form of protease inhibitors directly interfere with the processing of viral proteins.
  • inhibitors of helicase and / or protease activity substances are used, which are administered in various forms in vivo orally, intravenously, intramuscularly, subcutaneously, in encapsulated form with or without cell specificity-bearing changes or otherwise and due to the application a particular application and dose regimen have low cytotoxicity and / or high selectivity for certain cells and organs, cause no or insignificant side effects, have a relatively high metabolic half-life and a relatively low clearance rate in the organism.
  • inhibitors of helicase and / or protease activity further substances are used which are produced totally synthetic, synthesized by gene therapy methods in vivo, prepared by genetic engineering methods in vitro or in microorganisms, and protected by chemical modifications against degradation processes. An isolation in natural form from microorganisms or other natural sources can also be carried out.
  • means are provided according to the invention, surprisingly affect the production of infectious progeny viruses by blocking the replication and maturation of different viruses and thus prevent the spread of systemic infection in the organism and further block the release of infectious virus from infected cells, limit the spread of virus infection in the organism, prevent the onset of disease and reduce the spread of infection in the organism (reducing viral load) contribute to the prevention of systemic virus infection immediately after contact with infectious biological samples, infected individuals or their immediate vicinity, the viremia both in a new infection and in ch and suppress the success of virus elimination by the own immune system and / or by known means which in combination with the helicase inhibitors and / or protease activity increase with similar or other action.
  • the protective groups of the inhibitors of helicase and / or protease activity can also be used in combination with other anti-viral drugs and other therapeutic regimens, such as interferon alpha / beta / gamma and variants thereof (for example, pegylated interferons), interleukins, Nukeloside analogues (lamivudine, cidovir, ribavirin and others), steroids, thymidikinase inhibitors (eg, Ganzyklovir), plasma exchange, thymosin alpha 1, vaccines, passive and active vaccination, therapeutic and prophylactic vaccination, glycyrrhizin, stem cell transplantation, organ transplants, nutritional therapy, immunosuppressants , Cyclosporins and derivatives thereof, amanditin and derivatives, interleukins and other cytokines, non-proteasome selective protease inhibitors, azathioprine, hemodialysis and highly active antiretroviral therapy ("HAART”) in
  • the inhibition of helicase and / or protease activity is used for the preparation of agents for the control / treatment and prevention of diseases as well as pathological phenomena caused by SARS-CoV and related coronaviruses caused by viral haemorrhagic fever ( VHF) in humans and animals, in particular in non-human primates (monkeys) and their related animals, such as, for example, infections with the representatives of the filoviruses, the Ebola virus and Marburg virus or those caused by infections with Lassa virus or Crimea / Congo haemorrhagic fever virus.
  • VHF viral haemorrhagic fever
  • novel antiviral agents of the invention in the treatment of viral hepatides, it is noted that the use of helicase-protected inhibitors of the invention and / or protease activity in the inhibition of transcription, assembly, maturation and release of progeny viruses ,
  • the use of inhibiting the multiplication of Flaviviridae is by the mechanisms a) blocking / reducing the assembly and release of new virions, b) blocking / reducing the infectivity of the released virions, c) blocking / reducing the spread of infection in cultured cells.
  • novel chloro- and fluoromethyl ketone derivatives of the above inhibitors suppress the propagation of progeny viruses in infected organs.
  • Another use of protected inhibitors of helicase and / or protease activity is the prevention of hepatitis viral infection in individuals at high risk of re-infection, for example, physicians and other risk personnel, drug addicts, travelers in highly endemic areas Hepatitis viruses, in the treatment of patients or for family members of chronic virus carriers.
  • An essential application is the use of inhibitors of helicase and / or protease activity for the preparation of agents or pharmaceutical preparations for inhibiting the transcription, release, maturation and replication of hepatitis viruses and for the production of medicaments for the treatment and prophylaxis of hepatitis ,
  • the invention also provides the use of protective helicase and / or protease inhibitors for the control / treatment of diseases / pathological phenomena caused by infections with retroviruses.
  • the diseases / pathological phenomena can be caused by infections with leukemia viruses, human T-cell leukemia viruses HTLV-I and HTLV-II or by infections with lentiviruses.
  • Another field of application of the invention is the control / treatment of AIDS, both in the early asymptomatic and in the advanced disease phase, by means of inhibitors of helicase and / or protease activity. These substances can also be used in combination with other anti-retroviral drugs, eg with reverse transcriptase blockers.
  • the combination with anti-retroviral therapies based on gene therapy interventions is also possible.
  • Another use results from the combination with intracellular immunization, such as the introduction of anti-HIV-1 / HI V-2 effective genes in stem cells and / or in peripheral CD4 + lymphocytes.
  • a prevention of disease outbreak and a reduction of the spread of infection in the organism (reduction of "viral load") of asymptomatic HIV-1 / HI V-2 seropositive and HIV-I / HI V-2 infected persons is also possible according to the invention.
  • the inhibitors of helicase and / or protease activity according to the invention can be used for the treatment / control / prevention of HIV-induced dementia, in particular for the prevention of HIV infection of neurons, glia and endothelial cells in capillaries of the brain.
  • Another use is to prevent the establishment of systemic HIV-I / HI V-2 infection immediately after contact with infectious virus (for example, needle-stick injuries with HIV-contaminated blood or blood products).
  • the principle solution of the problem is shown by the example of HIV-1 and HIV-2. It is shown that immediately after the addition of different classes of compounds of protected inhibitors of helicase and / or protease activity in the following production of infectious virus particles is inhibited.
  • this phenomenon is observed in HIV-I infected permanent cultures of CD4 + human T cells transfected with infectious proviral DNA HIV-I and described in more detail here. Because of these novel activities of the inhibitors of viral transcription and processing according to the invention, it can be assumed that the application of inhibitors of helicase and / or protease activity provided with protective groups in vivo can suppress or completely eliminate the spread of infection of HIV in the organism.
  • the inhibitory effect of inhibitors of helicase and / or protease activity by chloro- and / or fluoromethyl ketones on the HIV replication includes the following mechanisms:
  • the defect in the processing of the viral precursor proteins triggered by protective groups with inhibitors of the helicase and / or protease activity is represented by means of biochemical methods.
  • the influence of the chloro- and / or fluoromethyl ketones according to the invention in the human lymphocyte system infected with human immunodeficiency virus (HIV) showed a dose-dependent inhibition of replication.
  • the inhibitory effect of the inhibitors of helicase and / or protease activity according to the invention on the virus replication in cultures of HIV-1 -infected CD4 + T cells is demonstrated.
  • the addition of nanoM concentrations to various classes of the inventive inhibitors of helicase and / or protease activity prevents the spread of infection and causes the lack of productive virus replication.
  • the principle of the use according to the invention of the inhibitors of helicase and / or protease activity according to the invention for blocking an HIV infection is novel with respect to the use of an already known class of substances (helicase and / or protease inhibitors provided with chemical protective groups). for a new activity (the blocking of gag processing and release of retroviruses). Furthermore, it is novel that the use of the inhibitors of helicase and / or protease activity according to the invention for the blocking of HIV and other retroviruses does not affect the virus itself, but mechanisms that are conserved in all host cells of the virus.
  • the mean survival time of an acute HIV-infected T cell is a few days.
  • the inhibition of virus release and the associated accumulation of partially toxic HIV proteins leads to an increased cytopathic effect and thereby to faster death of the infected cell.
  • the effect of the inhibitors of helicase and / or protease activity according to the invention should also lead to a faster death of already infected cells.
  • the reduced release of even a few or even non-infectious virus particles has a net effect with simultaneous cell death of the virus-producing cells in the case of in vivo use of the helicase inhibitors according to the invention. and / or protease activity reduces the amount of infectious virions in the peripheral blood and at the same time reduces the number of infected producer cells of HIV in the whole organism.
  • the principle solution of the problem is shown by the examples of HIV viruses. In control experiments it was first shown that pretreatment of the target cells (CD4 + T cells) with non-cytotoxic concentrations of different substance classes of inhibitors of helicase and / or protease activity has no influence on the viability of the host cell.
  • FIG. 1 The inhibition of HIV replication in the HLT system is shown in FIG. 1:
  • the human tonsil was cut into 3-5mm blocks after the ectomy and each 9 of these blocks were placed on gel sponges for further cultivation. Each block was infected with 10ng of HIV for 24h with concomitant administration of 50 ⁇ M AAPFcmk. A 3-fold determination was carried out per batch. After 24 hours, the virus was washed out and the blocks cultured for a further 15 days in RPMI medium. Supernatants were taken every 3 days for RT activity determination and new culture medium added.
  • Chloromethyl ketones have a very strong, dose-dependent potential for inhibiting the growth of ras-transformed cells.
  • Nuclear scaffold-associated protease in situ nuclear localization and effects of a proteasome inhibitor on growth and morphology of a ras-transformed hepatocyte cell line. Hepatology 22 (4 Pt l): 1230-5.

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  • Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des agents pour traiter des infections aiguës et chroniques par des virus pathogènes pour l'homme et les animaux, qui se fixent sur la membrane des cellules et sont libérés de la surface des cellules par bourgeonnement. Parmi ces virus figurent en particulier des agents pathogènes de maladies infectieuses telles que le SIDA, l'hépatite, la fièvre hémorragique, le SARS, la variole, la rougeole, la polio ou la grippe. Cette invention concerne des agents présentant une structure leur permettant d'agir sur les protéases et/ou les hélicases. Ainsi, ces inhibiteurs et leurs dérivés chlorométhylcétone et fluorométhylcétone influent sur la réplication intervenant dans des maladies virales. Parmi ces inhibiteurs figurent entre autres les classes de substances et les dérivés suivants : AAPF<SUB>CMK, </SUB> Z-VAD<SUB>FMK,</SUB> IETD<SUB>FMK,</SUB> Ac-YVAD<SUB>CMK,</SUB> VEID<SUB>FMK, </SUB> VPF<SUB>CMK, </SUB>LLF<SUB>CMK,</SUB> AAF<SUB>CMK, </SUB> AAPY<SUB>CMK</SUB> et GGL<SUB>CMK.</SUB> Ces agents perturbent les processus d'interaction entre les virus et les enzymes cellulaires qui sont nécessaires à la réplication virale, ce qui réduit voire supprime totalement la libération et la production de virus infectieux de descendance.
PCT/EP2007/058628 2006-08-18 2007-08-20 Utilisation de dérivés chlorométhylcétone et fluorométhylcétone dans des traitements antiviraux WO2008020085A2 (fr)

Applications Claiming Priority (2)

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DE102006039148A DE102006039148A1 (de) 2006-08-18 2006-08-18 Verwendung von Chloro- und Fluoromethylketon-Derivaten in der anti-viralen Therapie
DE102006039148.9 2006-08-18

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WO2008020085A2 true WO2008020085A2 (fr) 2008-02-21
WO2008020085A3 WO2008020085A3 (fr) 2008-07-31

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WO2009103821A2 (fr) * 2008-02-23 2009-08-27 Virologik Gmbh Agents pour le traitement d'infections virales

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WO2005087251A1 (fr) * 2004-03-10 2005-09-22 Clawnor, Inc. Compositions et methodes permettant d'inhiber une croissance cellulaire anormale

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WO2005087251A1 (fr) * 2004-03-10 2005-09-22 Clawnor, Inc. Compositions et methodes permettant d'inhiber une croissance cellulaire anormale

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DRUBIN ET AL: "A Protease Inhibitor Specifically Inhibits Growth of HPV-Infected Keratinocytes" MOLECULAR THERAPY, ACADEMIC PRESS, SAN DIEGO, CA, US, Bd. 13, Nr. 6, 1. Juni 2006 (2006-06-01), Seiten 1142-1148, XP005469388 ISSN: 1525-0016 in der Anmeldung erwähnt *
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DE102006039148A1 (de) 2008-02-21

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