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WO2025168575A1 - Inhibiteurs de la biosynthèse du nad pour le traitement d'infections par le virus de la dengue - Google Patents

Inhibiteurs de la biosynthèse du nad pour le traitement d'infections par le virus de la dengue

Info

Publication number
WO2025168575A1
WO2025168575A1 PCT/EP2025/052839 EP2025052839W WO2025168575A1 WO 2025168575 A1 WO2025168575 A1 WO 2025168575A1 EP 2025052839 W EP2025052839 W EP 2025052839W WO 2025168575 A1 WO2025168575 A1 WO 2025168575A1
Authority
WO
WIPO (PCT)
Prior art keywords
denv
gck
gckr
replication
nad
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/052839
Other languages
English (en)
Inventor
Olivier DIAZ
Cyrille Mathieu
Pierre-Olivier Vidalain
Vincent Lotteau
Eva-Isméry OGIRE
Laure PERRIN-COCON
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Ecole Normale Superieure de Lyon
Universite Claude Bernard Lyon 1
Original Assignee
Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Ecole Normale Superieure de Lyon
Universite Claude Bernard Lyon 1
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centre National de la Recherche Scientifique CNRS, Institut National de la Sante et de la Recherche Medicale INSERM, Ecole Normale Superieure de Lyon, Universite Claude Bernard Lyon 1 filed Critical Centre National de la Recherche Scientifique CNRS
Publication of WO2025168575A1 publication Critical patent/WO2025168575A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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

Definitions

  • Viruses depend on host cell metabolism to acquire the energy and metabolites they need for their replication. They feed on cellular resources but in many cases, they have also evolved mechanisms to actively induce metabolic reprogramming to meet their needs, modulating the expression or activity of numerous metabolic enzymes[l-3]. Viruses interfere especially with central carbon metabolism (CCM;[4, 5]) including glycolysis which produces both ATP and intermediate metabolites required for the biosynthesis of complex molecules.
  • CCM central carbon metabolism
  • these studies have identified key enzymatic cascades essential for virus replication. This provides basic knowledge on metabolic pathways and virus-host interactions, but has led also to the development of innovative therapeutic approaches based on the targeting of host cell metabolism to restrict viral growth.
  • the term “dengue virus” or “DENV” as is general meaning in the art and denotes an RNA virus of the family Flaviviridae genus Flavivirus. Other members of the same genus include yellow fever virus, West Nile virus, St. Louis encephalitis virus, Japanese encephalitis virus, tick-borne encephalitis virus, Kyasanur forest disease virus, and Omsk hemorrhagic fever virus. Most are transmitted by arthropods (mosquitoes or ticks), and are therefore also referred to as arboviruses (arthropod-borne viruses). According to the present invention, the dengue virus may be of any serotype, i.e. serotype 1, 2, 3 or 4.
  • the term "subject” or “patient” and “subject in need thereof” or “patient in need thereof”, is intended for a human or non-human mammal infected or likely to be infected with a dengue virus.
  • NAMPT refers to the nicotinamide phosphoribosyltransferase that catalyzes the first reversible step in NAD biosynthesis and nicotinamide (NAM) salvage.
  • the enzyme is designed for efficient capture of nicotinamide by coupling of ATP hydrolysis to assist in extraordinary NAM binding affinity and formation of NMN.
  • NAMPT provides the mechanism to replenish the NAD pool in human metabolism.
  • the structure of NAMPT is described further in, for example, Kim, et al. J Mol Biol.; 362:66-77 (2006).
  • DNA polymerase inhibitors may include idoxuridine, vidarabine, phosphonoacetic acid, trifluridine, acyclovir, forscarnet, ganciclovir, penciclovir, cidoclovir, famciclovir, valaciclovir and valganciclovir.
  • Signal transduction inhibitors include resveratrol and ribavirin.
  • TCID50 tissue culture infectious dose 50
  • GCK-GCKR interaction inhibitor AMG-3969
  • DENV replication data not shown
  • GCKR was overexpressed in order to limit GCK activity in Huh7 -GCK /HK2 ⁇ cells, resulting in reduced DENV replication (data not shown).
  • Mutations that impact GCKR’s capacity to interact with GCK have been described in the literature.
  • mutation D413A in GCKR was reported to decrease its capacity to inhibit GCK[38]
  • overexpression of the GCKR D413A mutant in YiuNI -GCK + /HK2 ⁇ cells had no effect on DENV replication (data not shown).
  • 6-Aminonicotinamide (6-AN) NAD+ is essential for glycolysis as it is used by GAPDH and lactate dehydrogenase (LDH) as a coenzyme.
  • 6-Aminonicotinamide (6-AN) is an inhibitor of NAD+ biosynthesis that affects several metabolic pathways including glycolysis and pentose phosphate pathway (PPP), as depicted in Figure 1A.
  • 6-AN inhibits DENV replication in hamster-derived organotypic liver cultures
  • 6-AN was associated with impaired NAD(H)-dependent glycolytic steps and inhibition of Zika virus replication [39]
  • the inventors have identified a mechanism by which DENV NS3 protein interferes with the activity of the hepatic GCKR protein, suggesting that DENV has selected a specific interaction that allows it to control glycolysis specifically in the hepatocyte, an interaction that has never been demonstrated for other members of the Flaviviridae family.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Le virus de la dengue (DENV) est un flavivirus porté par les moustiques, responsable de la dengue. Des études ont montré que le DENV interagit avec des voies métaboliques, en particulier la glycolyse est augmentée dans les cellules infectées par DENV. Cependant, la dépendance de DENV sur cette voie n'a pas été étudiée en détails. Les inventeurs ont identifié une interaction entre la protéine non structurale 3 (NS3) de DENV et de GCKR, une protéine hôte qui régule l'hexokinase GCK spécifique du foie. L'expression de NS3 seule a été trouvée pour augmenter la consommation de glucose et la sécrétion de lactate dans une lignée cellulaire hépatique exprimant GCK. Les inventeurs ont observé que l'interaction GCKR avec GCK diminue la réplication DENV, prenant en charge le rôle de NS3 en tant qu'inhibiteur de la fonction GCKR. En ciblant la biosynthèse de NAD(H) avec l'antimétabolite 6-amino-Nicotinamide (6-AN), les inventeurs ont diminué l'activité glycolytique cellulaire et inhibent la réplication du DENV dans la cellule hépatique. La présente invention concerne ainsi l'utilisation d'inhibiteurs de la biosynthèse de NAD pour le traitement d'infections par le virus de la dengue.
PCT/EP2025/052839 2024-02-05 2025-02-04 Inhibiteurs de la biosynthèse du nad pour le traitement d'infections par le virus de la dengue Pending WO2025168575A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP24305196 2024-02-05
EP24305196.8 2024-02-05

Publications (1)

Publication Number Publication Date
WO2025168575A1 true WO2025168575A1 (fr) 2025-08-14

Family

ID=90123100

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2025/052839 Pending WO2025168575A1 (fr) 2024-02-05 2025-02-04 Inhibiteurs de la biosynthèse du nad pour le traitement d'infections par le virus de la dengue

Country Status (1)

Country Link
WO (1) WO2025168575A1 (fr)

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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