Eric Arnoult - Academia.edu (original) (raw)
Papers by Eric Arnoult
Nature, 2011
Tuberculosis (TB) is more prevalent in the world today than at any other time in human history. M... more Tuberculosis (TB) is more prevalent in the world today than at any other time in human history. Mycobacterium tuberculosis, the pathogen responsible for TB, uses diverse strategies to survive in a variety of host lesions and to evade immune surveillance. A key question is how robust are our approaches to discovering new TB drugs, and what measures could be taken to reduce the long and protracted clinical development of new drugs. The emergence of multi-drug-resistant strains of M. tuberculosis makes the discovery of new molecular scaffolds a priority, and the current situation even necessitates the re-engineering and repositioning of some old drug families to achieve effective control. Whatever the strategy used, success will depend largely on our proper understanding of the complex interactions between the pathogen and its human host. In this review, we discuss innovations in TB drug discovery and evolving strategies to bring newer agents more quickly to patients.
Nature Chemical Biology, 2015
Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young chil... more Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. Here we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitors or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors.
The overall performance (efficiency, noise, gas pulsation, …) of piston compressors is strongly i... more The overall performance (efficiency, noise, gas pulsation, …) of piston compressors is strongly influenced by valve dynamics. In general, the dynamic behavior of the valve is modeled using finite element methods. While the free vibration of the valve can be accurately investigated using this technique, the simulation of the overall dynamics of the valve has to include a number of non-linear phenomena which influence the behavior. The most important are: the impacts, the oil stiction, the gas flow through the ports, the gas pulsation. An accurate numerical model of the dynamic behavior of valves has to account for all these phenomena. This increases the accuracy of input data, but increases the computation time to such an extent that it limits the use of such simulation software in the valve design process.
Antiviral Research, 2009
... Only a short stretch of DNA is synthesized when the growing DNA reaches Dirk Jochmans, Johan ... more ... Only a short stretch of DNA is synthesized when the growing DNA reaches Dirk Jochmans, Johan Vingerhoets, and Luc Geeraert Tibotec BVBA, Gen De ... HIV-1 resistant to the three currently available NNRTIs as well as a broad panel of HIV-1 clades (P. Bonneau, PA Robinson ...
Journal of medicinal chemistry, Jan 20, 2007
We previously reported the discovery of substituted benzimidazole fusion inhibitors with nanomola... more We previously reported the discovery of substituted benzimidazole fusion inhibitors with nanomolar activity against respiratory syncytial virus (Andries, K.; et al. Antiviral Res. 2003, 60, 209-219). A lead compound of the series was selected for preclinical evaluation. This drug candidate, JNJ-2408068 (formerly R170591, 1), showed long tissue retention times in several species (rat, dog, and monkey), creating cause for concern. We herein describe the optimization program to develop compounds with improved properties in terms of tissue retention. We have identified the aminoethyl-piperidine moiety as being responsible for the long tissue retention time of 1. We have investigated the replacement or the modification of this group, and we suggest that the pKa of this part of the molecules influences both the antiviral activity and the pharmacokinetic profile. We were able to identify new respiratory syncytial virus inhibitors with shorter half-lives in lung tissue.
Proceedings of the National Academy of Sciences, 2010
Accession: The atomic coordinates and structure factors for the reported crystal structure have b... more Accession: The atomic coordinates and structure factors for the reported crystal structure have been deposited in the RSCB Protein Data Bank under PDB ID 3KPE.
Nature, 2011
Tuberculosis (TB) is more prevalent in the world today than at any other time in human history. M... more Tuberculosis (TB) is more prevalent in the world today than at any other time in human history. Mycobacterium tuberculosis, the pathogen responsible for TB, uses diverse strategies to survive in a variety of host lesions and to evade immune surveillance. A key question is how robust are our approaches to discovering new TB drugs, and what measures could be taken to reduce the long and protracted clinical development of new drugs. The emergence of multi-drug-resistant strains of M. tuberculosis makes the discovery of new molecular scaffolds a priority, and the current situation even necessitates the re-engineering and repositioning of some old drug families to achieve effective control. Whatever the strategy used, success will depend largely on our proper understanding of the complex interactions between the pathogen and its human host. In this review, we discuss innovations in TB drug discovery and evolving strategies to bring newer agents more quickly to patients.
Journal of Medicinal Chemistry, 2005
To exploit available structural information about the cyclooxygenase enzyme for the virtual scree... more To exploit available structural information about the cyclooxygenase enzyme for the virtual screening of large chemical libraries, a docking-scoring protocol was tuned and validated. The screening accuracy was assessed using a series of known inhibitors and a set of diverse a priori inactive compounds that was seeded with known active ligands. The major parameters of the DOCK algorithm were investigated. A large improvement of the results was obtained on tweaking some of them. The generated complexes were rescored using six scoring functions. In this way, the striking importance of this step was demonstrated, as well as the good performances of DOCK energy and SCORE for this target. The results were further improved via a consensus approach. As a first application, a subset of a large compound library was screened using this protocol. Among the compounds that were selected for biological testing, a third of them turned out to have a significant enzyme inhibition.
Journal of Medicinal Chemistry, 2008
A preceding paper (Bonfanti et al. J. Med Chem. 2007, 50, 4572-4584) reported the optimization of... more A preceding paper (Bonfanti et al. J. Med Chem. 2007, 50, 4572-4584) reported the optimization of the pharmacokinetic profile of substituted benzimidazoles by reducing their tissue retention. However, the modifications that were necessary to achieve this goal also led to a significant drop in anti-RSV activity. This paper describes a molecular modeling study followed by a lead optimization program that led to the recovery of the initial potent antiviral activity and the selection of TMC353121 as a clinical candidate.
Journal of Ethnopharmacology, 2002
In our efforts to find new active tyrosinase inhibitors for skin-whitening or antibrowning prepar... more In our efforts to find new active tyrosinase inhibitors for skin-whitening or antibrowning preparations, we investigated 67 tropical plants belonging to 38 families, which were evaluated for their anti-tyrosinase activity. The results of our investigation show that extracts of 5 plants, Stryphnodendron barbatimao, Portulaca pilosa, Cariniana brasiliensis, Entada africana and Prosopis africana present interesting in vitro mushroom tyrosinase inhibition (over 90%), similar to a positive control: Morus alba . These 5 plants will be studied in order to isolate and identify phytochemical compounds, involved in this biological activity. #
Journal of Chemical Information and Modeling, 2004
Using classification (SOM, LVQ, Binary, Decision Tree) and regression algorithms (PLS, BRANN, k-N... more Using classification (SOM, LVQ, Binary, Decision Tree) and regression algorithms (PLS, BRANN, k-NN, Linear), this paper details the building of eight 2D-QSAR models from a 266 COX-2 inhibitor training set. The predictive performances of these eight models were subsequently compared using an 88 COX-2 inhibitor test set. Each ligand is described by 52 2D descriptors expressed as van der Waals Surface Areas (P_VSA) and its COX-2 binding IC50. One of our best predictive models is the neural network model (BRANN), which is able to select a subset, from the 88 ligand test set, that contains 94% COX-2 active inhibitors (pIC50>7.5) and detects 71% of all the actives. We then introduce a QSAR consensus prediction protocol that is shown to be more predictive than any single QSAR model: our C3 consensus approach is able to select a subset from the 88 ligand test set that contains 94% active inhibitors and 83% of all the actives. The 2D QSAR consensus protocol was finally applied to the high-throughput virtual screening of the NCI database, containing 193,477 organic compounds.
European Biophysics Journal, 2002
The genome of all retroviruses consists of two identical copies of an RNA sequence associated in ... more The genome of all retroviruses consists of two identical copies of an RNA sequence associated in a non-covalent dimer. A region upstream from the splice donor (SL1) comprising a self-complementary sequence is responsible for the initiation of the dimerization. This region is able to dimerize in two conformations: a loop-loop complex or an extended duplex. Here, we solve by 2D NMR techniques the solution structure of a 23-nucleotide sequence corresponding to HIV-1 SL1 Lai in which the mutation G12 A12 is included to prevent dimerization. It is shown that this monomer adopts a stem-loop conformation with a seven base pairs stem and a nine nucleotide loop containing the G10 C11 A12 C13 G14 C15 sequence. The stem is well structured in an A-form duplex, while the loop is more flexible even though elements of structure are evident. We show that the structure adopted by the stem can be appreciably different from its relaxed structure when the adenines A8, A9 and A16 in the loop are mechanically constrained. This point could be important for the efficiency of the dimerization. This experimental study is complemented with a 10 ns molecular dynamics simulation in the presence of counterions and explicit water molecules. This simulation brings about information on the flexibility of the loop, such as a hinge motion between the stem and the loop and a labile lattice of hydrogen bonds in the loop. The bases of the nucleotides G10 to C15 were found outside of the loop during a part of the trajectory, which is certainly necessary to initiate the dimerization process of the genuine SL1 Lai sequence.
Page 1. Methods and Principles in Medicinal Chemistry Edited by Chrisloph Sotriffer ffiWILEY-VCH ... more Page 1. Methods and Principles in Medicinal Chemistry Edited by Chrisloph Sotriffer ffiWILEY-VCH Virtual Screening Page 2. Methods and Principles in Medicinal Chemistry Edited by Christoph Sotriffer ®WILEY"VCH Virtual Screening Page 3. ...
Annales de Dermatologie et de Vénéréologie, 2005
Journal of Medicinal Chemistry, 2011
This paper reports the synthesis and antiviral properties of new difluoromethylbenzoxazole (DFMB)... more This paper reports the synthesis and antiviral properties of new difluoromethylbenzoxazole (DFMB) pyrimidine thioether derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors. By use of a combination of structural biology study and traditional medicinal chemistry, several members of this novel class were synthesized using a single electron transfer chain process (radical nucleophilic substitution, S RN 1) and were found to be potent against wild-type HIV-1 reverse transcriptase, with low cytotoxicity but with moderate activity against drug-resistant strains. The most promising compound 24 showed a significant EC 50 value close to 6.4 nM against HIV-1 IIIB, a moderate EC 50 value close to 54 μM against an NNRTI resistant double mutant (K103N + Y181C), but an excellent selectivity index >15477 (CC 50 > 100 μM).
Nature, 2011
Tuberculosis (TB) is more prevalent in the world today than at any other time in human history. M... more Tuberculosis (TB) is more prevalent in the world today than at any other time in human history. Mycobacterium tuberculosis, the pathogen responsible for TB, uses diverse strategies to survive in a variety of host lesions and to evade immune surveillance. A key question is how robust are our approaches to discovering new TB drugs, and what measures could be taken to reduce the long and protracted clinical development of new drugs. The emergence of multi-drug-resistant strains of M. tuberculosis makes the discovery of new molecular scaffolds a priority, and the current situation even necessitates the re-engineering and repositioning of some old drug families to achieve effective control. Whatever the strategy used, success will depend largely on our proper understanding of the complex interactions between the pathogen and its human host. In this review, we discuss innovations in TB drug discovery and evolving strategies to bring newer agents more quickly to patients.
Nature Chemical Biology, 2015
Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young chil... more Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. Here we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitors or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors.
The overall performance (efficiency, noise, gas pulsation, …) of piston compressors is strongly i... more The overall performance (efficiency, noise, gas pulsation, …) of piston compressors is strongly influenced by valve dynamics. In general, the dynamic behavior of the valve is modeled using finite element methods. While the free vibration of the valve can be accurately investigated using this technique, the simulation of the overall dynamics of the valve has to include a number of non-linear phenomena which influence the behavior. The most important are: the impacts, the oil stiction, the gas flow through the ports, the gas pulsation. An accurate numerical model of the dynamic behavior of valves has to account for all these phenomena. This increases the accuracy of input data, but increases the computation time to such an extent that it limits the use of such simulation software in the valve design process.
Antiviral Research, 2009
... Only a short stretch of DNA is synthesized when the growing DNA reaches Dirk Jochmans, Johan ... more ... Only a short stretch of DNA is synthesized when the growing DNA reaches Dirk Jochmans, Johan Vingerhoets, and Luc Geeraert Tibotec BVBA, Gen De ... HIV-1 resistant to the three currently available NNRTIs as well as a broad panel of HIV-1 clades (P. Bonneau, PA Robinson ...
Journal of medicinal chemistry, Jan 20, 2007
We previously reported the discovery of substituted benzimidazole fusion inhibitors with nanomola... more We previously reported the discovery of substituted benzimidazole fusion inhibitors with nanomolar activity against respiratory syncytial virus (Andries, K.; et al. Antiviral Res. 2003, 60, 209-219). A lead compound of the series was selected for preclinical evaluation. This drug candidate, JNJ-2408068 (formerly R170591, 1), showed long tissue retention times in several species (rat, dog, and monkey), creating cause for concern. We herein describe the optimization program to develop compounds with improved properties in terms of tissue retention. We have identified the aminoethyl-piperidine moiety as being responsible for the long tissue retention time of 1. We have investigated the replacement or the modification of this group, and we suggest that the pKa of this part of the molecules influences both the antiviral activity and the pharmacokinetic profile. We were able to identify new respiratory syncytial virus inhibitors with shorter half-lives in lung tissue.
Proceedings of the National Academy of Sciences, 2010
Accession: The atomic coordinates and structure factors for the reported crystal structure have b... more Accession: The atomic coordinates and structure factors for the reported crystal structure have been deposited in the RSCB Protein Data Bank under PDB ID 3KPE.
Nature, 2011
Tuberculosis (TB) is more prevalent in the world today than at any other time in human history. M... more Tuberculosis (TB) is more prevalent in the world today than at any other time in human history. Mycobacterium tuberculosis, the pathogen responsible for TB, uses diverse strategies to survive in a variety of host lesions and to evade immune surveillance. A key question is how robust are our approaches to discovering new TB drugs, and what measures could be taken to reduce the long and protracted clinical development of new drugs. The emergence of multi-drug-resistant strains of M. tuberculosis makes the discovery of new molecular scaffolds a priority, and the current situation even necessitates the re-engineering and repositioning of some old drug families to achieve effective control. Whatever the strategy used, success will depend largely on our proper understanding of the complex interactions between the pathogen and its human host. In this review, we discuss innovations in TB drug discovery and evolving strategies to bring newer agents more quickly to patients.
Journal of Medicinal Chemistry, 2005
To exploit available structural information about the cyclooxygenase enzyme for the virtual scree... more To exploit available structural information about the cyclooxygenase enzyme for the virtual screening of large chemical libraries, a docking-scoring protocol was tuned and validated. The screening accuracy was assessed using a series of known inhibitors and a set of diverse a priori inactive compounds that was seeded with known active ligands. The major parameters of the DOCK algorithm were investigated. A large improvement of the results was obtained on tweaking some of them. The generated complexes were rescored using six scoring functions. In this way, the striking importance of this step was demonstrated, as well as the good performances of DOCK energy and SCORE for this target. The results were further improved via a consensus approach. As a first application, a subset of a large compound library was screened using this protocol. Among the compounds that were selected for biological testing, a third of them turned out to have a significant enzyme inhibition.
Journal of Medicinal Chemistry, 2008
A preceding paper (Bonfanti et al. J. Med Chem. 2007, 50, 4572-4584) reported the optimization of... more A preceding paper (Bonfanti et al. J. Med Chem. 2007, 50, 4572-4584) reported the optimization of the pharmacokinetic profile of substituted benzimidazoles by reducing their tissue retention. However, the modifications that were necessary to achieve this goal also led to a significant drop in anti-RSV activity. This paper describes a molecular modeling study followed by a lead optimization program that led to the recovery of the initial potent antiviral activity and the selection of TMC353121 as a clinical candidate.
Journal of Ethnopharmacology, 2002
In our efforts to find new active tyrosinase inhibitors for skin-whitening or antibrowning prepar... more In our efforts to find new active tyrosinase inhibitors for skin-whitening or antibrowning preparations, we investigated 67 tropical plants belonging to 38 families, which were evaluated for their anti-tyrosinase activity. The results of our investigation show that extracts of 5 plants, Stryphnodendron barbatimao, Portulaca pilosa, Cariniana brasiliensis, Entada africana and Prosopis africana present interesting in vitro mushroom tyrosinase inhibition (over 90%), similar to a positive control: Morus alba . These 5 plants will be studied in order to isolate and identify phytochemical compounds, involved in this biological activity. #
Journal of Chemical Information and Modeling, 2004
Using classification (SOM, LVQ, Binary, Decision Tree) and regression algorithms (PLS, BRANN, k-N... more Using classification (SOM, LVQ, Binary, Decision Tree) and regression algorithms (PLS, BRANN, k-NN, Linear), this paper details the building of eight 2D-QSAR models from a 266 COX-2 inhibitor training set. The predictive performances of these eight models were subsequently compared using an 88 COX-2 inhibitor test set. Each ligand is described by 52 2D descriptors expressed as van der Waals Surface Areas (P_VSA) and its COX-2 binding IC50. One of our best predictive models is the neural network model (BRANN), which is able to select a subset, from the 88 ligand test set, that contains 94% COX-2 active inhibitors (pIC50>7.5) and detects 71% of all the actives. We then introduce a QSAR consensus prediction protocol that is shown to be more predictive than any single QSAR model: our C3 consensus approach is able to select a subset from the 88 ligand test set that contains 94% active inhibitors and 83% of all the actives. The 2D QSAR consensus protocol was finally applied to the high-throughput virtual screening of the NCI database, containing 193,477 organic compounds.
European Biophysics Journal, 2002
The genome of all retroviruses consists of two identical copies of an RNA sequence associated in ... more The genome of all retroviruses consists of two identical copies of an RNA sequence associated in a non-covalent dimer. A region upstream from the splice donor (SL1) comprising a self-complementary sequence is responsible for the initiation of the dimerization. This region is able to dimerize in two conformations: a loop-loop complex or an extended duplex. Here, we solve by 2D NMR techniques the solution structure of a 23-nucleotide sequence corresponding to HIV-1 SL1 Lai in which the mutation G12 A12 is included to prevent dimerization. It is shown that this monomer adopts a stem-loop conformation with a seven base pairs stem and a nine nucleotide loop containing the G10 C11 A12 C13 G14 C15 sequence. The stem is well structured in an A-form duplex, while the loop is more flexible even though elements of structure are evident. We show that the structure adopted by the stem can be appreciably different from its relaxed structure when the adenines A8, A9 and A16 in the loop are mechanically constrained. This point could be important for the efficiency of the dimerization. This experimental study is complemented with a 10 ns molecular dynamics simulation in the presence of counterions and explicit water molecules. This simulation brings about information on the flexibility of the loop, such as a hinge motion between the stem and the loop and a labile lattice of hydrogen bonds in the loop. The bases of the nucleotides G10 to C15 were found outside of the loop during a part of the trajectory, which is certainly necessary to initiate the dimerization process of the genuine SL1 Lai sequence.
Page 1. Methods and Principles in Medicinal Chemistry Edited by Chrisloph Sotriffer ffiWILEY-VCH ... more Page 1. Methods and Principles in Medicinal Chemistry Edited by Chrisloph Sotriffer ffiWILEY-VCH Virtual Screening Page 2. Methods and Principles in Medicinal Chemistry Edited by Christoph Sotriffer ®WILEY"VCH Virtual Screening Page 3. ...
Annales de Dermatologie et de Vénéréologie, 2005
Journal of Medicinal Chemistry, 2011
This paper reports the synthesis and antiviral properties of new difluoromethylbenzoxazole (DFMB)... more This paper reports the synthesis and antiviral properties of new difluoromethylbenzoxazole (DFMB) pyrimidine thioether derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors. By use of a combination of structural biology study and traditional medicinal chemistry, several members of this novel class were synthesized using a single electron transfer chain process (radical nucleophilic substitution, S RN 1) and were found to be potent against wild-type HIV-1 reverse transcriptase, with low cytotoxicity but with moderate activity against drug-resistant strains. The most promising compound 24 showed a significant EC 50 value close to 6.4 nM against HIV-1 IIIB, a moderate EC 50 value close to 54 μM against an NNRTI resistant double mutant (K103N + Y181C), but an excellent selectivity index >15477 (CC 50 > 100 μM).