Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication

Autor: Bruno Canard, Johan Neyts, Céline Durafour, Loic Roux, Stéphane Priet, Nadine Payrot, Karine Barral, Fabien Zoulim, Karine Alvarez, Clément Weck, Jan Balzarini
Přispěvatelé: Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Equipe 15, Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Virus des hépatites et pathologies associées, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Microbiology and Immunology, Rega Institute for Medical Research, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Laboratory of Medicinal Chemistry, Rega Institute-Catholic University of Leuven, Architecture et fonction des macromolécules biologiques (AFMB), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon], equipe 15, Service d'hépatologie et de gastroentérologie, Hospices Civils de Lyon (HCL)-Hôtel-Dieu-Hospices Civils de Lyon (HCL)-Hôtel-Dieu-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Rega Institute for Medical Research [Leuven, België], Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), Hospices Civils de Lyon (HCL)-Hôtel-Dieu-Hospices Civils de Lyon (HCL)-Hôtel-Dieu-Centre de Recherche en Cancérologie de Lyon (CRCL), Rega Institute for Medical Research, Rega Institute for medical research, Centre de Recherche en Cancérologie de Marseille (CRCM / U891 Inserm), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Architecture et fonction des Macromolécules Biologiques - UMR 6098 (AFMB), Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Magnetic Resonance Spectroscopy
[CHIM.THER]Chemical Sciences/Medicinal Chemistry
Spectrometry
Mass
Fast Atom Bombardment
medicine.disease_cause
Virus Replication
MESH: HIV-1
chemistry.chemical_compound
(R)-PMPA
(R)-9-[2-phosphonomethoxypropyl]adenine
Drug Stability
Drug Discovery
HBV
Thiophosphonate
Antiviral activity
MOI
multiplicity of infection
Chromatography
High Pressure Liquid
ComputingMilieux_MISCELLANEOUS
chemistry.chemical_classification
dNTP
deoxynucleotide
0303 health sciences
TCID50
50% tissue culture infectious dose
Modified nucleotide
General Medicine
Nuclear magnetic resonance spectroscopy
NRTIs
nucleoside RT inhibitors
3. Good health
HIV
human immunodeficiency virus
MESH: Hepatitis B virus
Biochemistry
PBMC
peripheral blood mononuclear cells
RT
reverse transcriptase
MESH: Organophosphonates
MESH: Antiviral Agents
Hepatitis B virus
ANPs
acyclic nucleoside phosphonates
Organophosphonates
[SDV.CAN]Life Sciences [q-bio]/Cancer
Peripheral blood mononuclear cell
Antiviral Agents
Article
Cell Line
03 medical and health sciences
NtRTIs
nucleotide RT inhibitors
MESH: Drug Stability
medicine
Humans
MESH: Spectrometry
Mass
Fast Atom Bombardment
[CHIM]Chemical Sciences
MESH: Chromatography
High Pressure Liquid
030304 developmental biology
Pharmacology
MESH: Humans
PMEA
9-[2-phosphonomethoxyethyl]adenine
030306 microbiology
MESH: Magnetic Resonance Spectroscopy
Organic Chemistry
MESH: Virus Replication
RNA
HIV
In vitro
MESH: Cell Line
Herpes simplex virus
Enzyme
HBV
hepatitis B virus
chemistry
Cell culture
HIV-1
DNA
Zdroj: European Journal of Medicinal Chemistry
European Journal of Medicinal Chemistry, Elsevier, 2011, 46 (9), pp.4281-4288. ⟨10.1016/j.ejmech.2011.06.034⟩
European Journal of Medicinal Chemistry, Elsevier, 2011, 46 (9), pp.4281-8. ⟨10.1016/j.ejmech.2011.06.034⟩
European Journal of Medicinal Chemistry, 2011, 46 (9), pp.4281-4288. ⟨10.1016/j.ejmech.2011.06.034⟩
ISSN: 0223-5234
1768-3254
DOI: 10.1016/j.ejmech.2011.06.034⟩
Popis: 9-[2-(Thiophosphonomethoxy)ethyl]adenine 3 and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine 4 were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the α-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA 3 and S-PMPA 4 were evaluated for in vitro activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity. We showed that their diphosphate forms S-PMEApp 5 and S-PMPApp 6 are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds 3 and 4 were evaluated for in vitro activity against a broad panel of DNA and RNA viruses and displayed beside HIV a moderate activity against herpes simplex virus and vaccinia viruses. In order to measure enzymatic stabilities of the target derivatives 3 and 4, kinetic data and decomposition pathways were studied at 37 °C in several media.
Graphical abstract Highlights ► The RT of HIV is an important target for antiretroviral drugs such as nucleosi(ti)de RT inhibitors. ► Two nucleotides (ANP) are currently used in HIV/HBV therapy: Adefovir (Hepsera) and Tenofovir (Viread). ► We have designed, synthesized and tested new ANPs: α-thiophosphonates named S-PMEA and S-PMPA. ► α-thiophosphonates display potent activity against HIV-1, clinical HIV-1 isolates, HIV-2 and HBV. ► S-PMEApp and S-PMPApp are potent inhibitors and readily incorporated by WT HIV-1 RT.
Databáze: OpenAIRE
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