DESIGN AND SYNTHESIS OF NONPEPTIDE PROTEASE INHIBITORS

Summary

Principal Investigator: Arun Ghosh
Abstract: DESCRIPTION (provided by applicant): The incorporation of HIV-1 protease inhibitors (PIs) in 1996 into combination therapy regimens with two or more reverse transcriptase inhibitors has been critical to the reduction of AIDS related mortality, improvement of quality of life, and enhancement of HIV/AIDS management. Highly active antiretroviral therapy (HAART) remains the most effective treatment option for HIV/AIDS, but there are many serious limitations of current treatment regimens. The emergence of multidrug-resistant HIV-1 variants is perhaps, one of the most formidable challenges. In our continuing collaborative research efforts toward developing new generations of protease inhibitors, our structure-based design strategies have led to the design and discovery of protease inhibitor UIC-94017 (later named TMC-114, or darunavir). Darunavir has exhibited marked antiviral activity, excellent drug resistance profiles against multidrug-resistant strains and favorable pharmacokinetic properties. On June 23, 2006, darunavir was approved by the FDA as the first treatment for drug-resistant HIV. Darunavir represents the first of a new generation of inhibitors to combat drug-resistant HIV. However, it is far from ideal for long-term effective treatment. Issues concerning oral bioavailability, pill-burden and possible emergence of resistance over time remain to be answered. Based upon our high resolution X-ray crystal structures of darunavir-bound HIV protease and a number of other protein-ligand structures, we have envisioned a number of intriguing design concepts and developed tools to combat drug-resistance. We have carried out preliminary structure-activity studies and generated a number of small molecule leads. This work now forms the basis of our proposed studies which include: (a) structure-based design and synthesis of bis-THF-derived and nonsulfonamide-based novel drug-like PIs;(b) design and development of novel ligands and scaffolds to improve pharmacological profiles of cyclopentyl-tetrahydrofuran (cp-THF)-derived PIs;(c) structure-based design and development of novel templates, scaffolds and heterocyclic ligands to generate novel small molecule drug-like PIs;(d) performance of in-depth drug-resistance studies and determination of X-ray structures of selected inhibitors to gain molecular insight. This research integrates organic synthesis, protein-ligand x-ray crystallography, molecular modeling and in-depth virus and cell-biological studies to design the next generation of HIV-1 protease inhibitors.
Funding Period: ----------------1996 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc An intramolecular cascade cyclization of 2-aryl indoles: efficient methods for the construction of 2,3-functionalized indolines and 3-indolinones
    Arun K Ghosh
    Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA
    Org Biomol Chem 12:3567-71. 2014
  2. pmc Stereoselective synthesis of both tetrahydropyran rings of the antitumor macrolide, (-)-lasonolide A
    Arun K Ghosh
    Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA
    J Org Chem 77:2559-65. 2012
  3. pmc Critical differences in HIV-1 and HIV-2 protease specificity for clinical inhibitors
    Yunfeng Tie
    Department of Biology, Georgia State University, Atlanta, Georgia 30303, USA
    Protein Sci 21:339-50. 2012
  4. pmc A stereoselective synthesis of (-)-viridiofungin A utilizing a TiCl(4)-promoted asymmetric multicomponent reaction
    Arun K Ghosh
    Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, USA
    Org Lett 14:510-2. 2012
  5. pmc Tetrahydrofuran, tetrahydropyran, triazoles and related heterocyclic derivatives as HIV protease inhibitors
    Arun K Ghosh
    Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA
    Future Med Chem 3:1181-97. 2011
  6. pmc Design of HIV-1 protease inhibitors with C3-substituted hexahydrocyclopentafuranyl urethanes as P2-ligands: synthesis, biological evaluation, and protein-ligand X-ray crystal structure
    Arun K Ghosh
    Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA
    J Med Chem 54:5890-901. 2011
  7. pmc GRL-0519, a novel oxatricyclic ligand-containing nonpeptidic HIV-1 protease inhibitor (PI), potently suppresses replication of a wide spectrum of multi-PI-resistant HIV-1 variants in vitro
    Masayuki Amano
    Departments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, Kumamoto, Japan
    Antimicrob Agents Chemother 57:2036-46. 2013
  8. pmc Synthesis and biological evaluation of novel allophenylnorstatine-based HIV-1 protease inhibitors incorporating high affinity P2-ligands
    Arun K Ghosh
    Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, United States
    Bioorg Med Chem Lett 20:1241-6. 2010
  9. pmc A convergent synthesis of the proposed structure of antitumor depsipeptide stereocalpin A
    Arun K Ghosh
    Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, USA
    Org Lett 11:1963-6. 2009
  10. ncbi BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease
    Arun K Ghosh
    Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA
    Chem Soc Rev 43:6765-813. 2014

Scientific Experts

  • Arun Ghosh
  • Hiroaki Mitsuya
  • Debananda Das
  • Yasuhiro Koh
  • Irene T Weber
  • Masayuki Amano
  • Yuan Fang Wang
  • Andrey Y Kovalevsky
  • Robert W Harrison
  • Yunfeng Tie
  • Manabu Aoki
  • Yasushi Tojo
  • Chun Xiao Xu
  • John M Louis
  • Sofiya Leschenko
  • Peter I Boross
  • Kalapala Venkateswara Rao
  • Johnson Agniswamy
  • Fengling Liu
  • Ravikiran S Yedidi
  • Kenji Maeda
  • Hirotomo Nakata
  • Jozsef Tozser
  • Jianfeng Li
  • Hongmei Zhang
  • Chen Hsiang Shen
  • Kazuhiko Ide
  • David A Davis
  • Ernest Hamel
  • Xiaoming Xu
  • A Jonathan Singh
  • Tam Luong Nguyen
  • Maki Nakayama
  • Hiromi Ogata-Aoki
  • Andrey Yu Kovalevsky
  • Sofiya Leshchenko
  • Hiroyuki Gatanaga
  • Jane M Sayer
  • Joseph Richard Campbell
  • Joshua D Kaufman
  • Paul T Wingfield
  • Stephen J Stahl
  • Harisha Garimella
  • Ira Palmer
  • Melinda Steffey
  • Pedro Miguel Salcedo-Gómez
  • W Sean Fyvie
  • Ting Yi Chiu
  • Robert W Shafer
  • Bruno Chapsal
  • Matthew L Danish
  • Hiromi Aoki-Ogata
  • Matthew Danish
  • Peter T Northcote
  • David D Anderson
  • Ariane Chan
  • Wakako Kamata
  • John H Miller
  • Sarang Kulkarni
  • Rick Gussio
  • Tomomi Towata
  • Lyndon M West
  • Michael Kruhlak
  • Anja Wilmes
  • Sofiya Leshchenko-Yashchuk
  • Annie Aniana
  • Shintaro Matsumi
  • Robert Yarchoan
  • Peter Boross
  • Abigail Baldridge
  • Tatsuo Shioda
  • Yasuhiro Suzuki
  • Damaris D Yeh
  • Khaja A Hussain

Detail Information

Publications66

  1. pmc An intramolecular cascade cyclization of 2-aryl indoles: efficient methods for the construction of 2,3-functionalized indolines and 3-indolinones
    Arun K Ghosh
    Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA
    Org Biomol Chem 12:3567-71. 2014
    ..The methods provided convenient access to fused imidazo[1,2-c]oxazolidinone, oxazolidine, or tetrahydro-1,3-oxazine cores under mild conditions. ..
  2. pmc Stereoselective synthesis of both tetrahydropyran rings of the antitumor macrolide, (-)-lasonolide A
    Arun K Ghosh
    Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA
    J Org Chem 77:2559-65. 2012
    ....
  3. pmc Critical differences in HIV-1 and HIV-2 protease specificity for clinical inhibitors
    Yunfeng Tie
    Department of Biology, Georgia State University, Atlanta, Georgia 30303, USA
    Protein Sci 21:339-50. 2012
    ..Moreover, this analysis provides a structural explanation for the weaker antiviral effects of APV on HIV-2...
  4. pmc A stereoselective synthesis of (-)-viridiofungin A utilizing a TiCl(4)-promoted asymmetric multicomponent reaction
    Arun K Ghosh
    Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, USA
    Org Lett 14:510-2. 2012
    ..Other key steps include an acyloxycarbonium ion-mediated tetrahydrofuran ring-opening reaction and a Julia-Kocienski olefination...
  5. pmc Tetrahydrofuran, tetrahydropyran, triazoles and related heterocyclic derivatives as HIV protease inhibitors
    Arun K Ghosh
    Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA
    Future Med Chem 3:1181-97. 2011
    ..This review will hopefully stimulate the widespread application of these heterocycles in the design of other therapeutic agents...
  6. pmc Design of HIV-1 protease inhibitors with C3-substituted hexahydrocyclopentafuranyl urethanes as P2-ligands: synthesis, biological evaluation, and protein-ligand X-ray crystal structure
    Arun K Ghosh
    Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA
    J Med Chem 54:5890-901. 2011
    ..Inhibitor 26 exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray structure of 26-bound HIV-1 protease revealed important molecular insight into the ligand-binding site interactions...
  7. pmc GRL-0519, a novel oxatricyclic ligand-containing nonpeptidic HIV-1 protease inhibitor (PI), potently suppresses replication of a wide spectrum of multi-PI-resistant HIV-1 variants in vitro
    Masayuki Amano
    Departments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, Kumamoto, Japan
    Antimicrob Agents Chemother 57:2036-46. 2013
    ....
  8. pmc Synthesis and biological evaluation of novel allophenylnorstatine-based HIV-1 protease inhibitors incorporating high affinity P2-ligands
    Arun K Ghosh
    Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, United States
    Bioorg Med Chem Lett 20:1241-6. 2010
    ..Inhibitors 3b and 3c, containing conformationally constrained cyclic ethers, displayed impressive enzymatic and antiviral properties and represent promising lead compounds for further optimization...
  9. pmc A convergent synthesis of the proposed structure of antitumor depsipeptide stereocalpin A
    Arun K Ghosh
    Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, USA
    Org Lett 11:1963-6. 2009
    ..A late-stage methylation strategy led to the synthesis of the proposed structure of stereocalpin A...
  10. ncbi BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease
    Arun K Ghosh
    Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA
    Chem Soc Rev 43:6765-813. 2014
    ....
  11. pmc Enantioselective syntheses of FR901464 and spliceostatin A: potent inhibitors of spliceosome
    Arun K Ghosh
    Department of Chemistry and Department of Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States
    Org Lett 15:5088-91. 2013
    ..Coupling of A- and B-ring fragments was accomplished via cross-metathesis. ..
  12. pmc Highly potent HIV-1 protease inhibitors with novel tricyclic P2 ligands: design, synthesis, and protein-ligand X-ray studies
    Arun K Ghosh
    Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
    J Med Chem 56:6792-802. 2013
    ....
  13. pmc P2' benzene carboxylic acid moiety is associated with decrease in cellular uptake: evaluation of novel nonpeptidic HIV-1 protease inhibitors containing P2 bis-tetrahydrofuran moiety
    Ravikiran S Yedidi
    Experimental Retrovirology Section
    Antimicrob Agents Chemother 57:4920-7. 2013
    ..The anti-HIV-1 potency, favorable toxicity, and binding profile of GRL008 suggest that further optimization of the P2' moiety may improve its antiretroviral features. ..
  14. pmc Extreme multidrug resistant HIV-1 protease with 20 mutations is resistant to novel protease inhibitors with P1'-pyrrolidinone or P2-tris-tetrahydrofuran
    Johnson Agniswamy
    Department of Biology, Molecular Basis of Disease Program, Georgia State University, Atlanta, Georgia 30303, USA
    J Med Chem 56:4017-27. 2013
    ..Overall, inhibitor 3 compares favorably with darunavir in affinity for PR20 and shows promise for further development...
  15. pmc Novel P2 tris-tetrahydrofuran group in antiviral compound 1 (GRL-0519) fills the S2 binding pocket of selected mutants of HIV-1 protease
    Hongmei Zhang
    Department of Biology, Georgia State University, Atlanta, Georgia 30303, USA
    J Med Chem 56:1074-83. 2013
    ..The carbonyl oxygen of Gly48 showed two alternative conformations in all structures likely due to the snug fit of the large tris-THF group in the S2 subsite in agreement with high antiviral efficacy of 1 on resistant virus...
  16. pmc Enantioselective total synthesis of (+)-lithospermic acid
    Arun K Ghosh
    Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, USA
    Org Lett 14:5046-9. 2012
    ....
  17. pmc Design and synthesis of stereochemically defined novel spirocyclic P2-ligands for HIV-1 protease inhibitors
    Arun K Ghosh
    Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, USA
    Org Lett 10:5135-8. 2008
    ..Structure-based design, synthesis of ligands, and biological evaluations of the resulting inhibitors are reported...
  18. ncbi Altered HIV-1 Gag protein interactions with cyclophilin A (CypA) on the acquisition of H219Q and H219P substitutions in the CypA binding loop
    Hiroyuki Gatanaga
    Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, NCI, National Institutes of Health, Bethesda, MD 20892, USA
    J Biol Chem 281:1241-50. 2006
    ....
  19. pmc Flexible cyclic ethers/polyethers as novel P2-ligands for HIV-1 protease inhibitors: design, synthesis, biological evaluation, and protein-ligand X-ray studies
    Arun K Ghosh
    Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA
    J Med Chem 51:6021-33. 2008
    ..In addition, the P2-ligand in 3d forms a unique water-mediated interaction with the NH of Gly-48...
  20. pmc Enantioselective total synthesis of (+)-largazole, a potent inhibitor of histone deacetylase
    Arun K Ghosh
    Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA
    Org Lett 10:3907-9. 2008
    ....
  21. ncbi Development of protease inhibitors and the fight with drug-resistant HIV-1 variants
    Hiroaki Mitsuya
    The Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA
    Adv Pharmacol 56:169-97. 2008
  22. pmc Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV
    Arun K Ghosh
    Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA
    Bioorg Med Chem 15:7576-80. 2007
    ..Darunavir has recently been approved for the treatment of HIV/AIDS patients harboring multidrug-resistant HIV-1 variants that do not respond to previously existing HAART regimens...
  23. ncbi Design of HIV protease inhibitors targeting protein backbone: an effective strategy for combating drug resistance
    Arun K Ghosh
    Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA
    Acc Chem Res 41:78-86. 2008
    ..The concept of targeting the protein backbone in current structure-based drug design may offer a reliable strategy for combating drug resistance...
  24. pmc Potent new antiviral compound shows similar inhibition and structural interactions with drug resistant mutants and wild type HIV-1 protease
    Yuan Fang Wang
    Department of Biology, Molecular Basis of Disease, Georgia State University, Atlanta, Georgia 30303, USA
    J Med Chem 50:4509-15. 2007
    ..Therefore, inhibitor 1 is a valuable addition to the antiviral inhibitors with high potency against resistant strains of HIV...
  25. ncbi Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization
    Yasuhiro Koh
    Department of Hematology, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, 1 1 1 Honjo, Kumamoto 860 8556, Japan
    J Biol Chem 282:28709-20. 2007
    ..Such a dual inhibition mechanism should lead to highly potent inhibition of HIV-1...
  26. pmc A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro
    Masayuki Amano
    Departments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, 1 1 1 Honjo, Kumamoto 860 8556, Japan
    Antimicrob Agents Chemother 51:2143-55. 2007
    ....
  27. ncbi Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir
    Yunfeng Tie
    Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA
    Proteins 67:232-42. 2007
    ..This analysis will assist with development of more effective antiviral inhibitors...
  28. pmc Asymmetric multicomponent reactions: diastereoselective synthesis of substituted pyrrolidines and prolines
    Arun K Ghosh
    Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA
    Org Lett 8:4509-11. 2006
    ..The reaction is quite efficient and constructed up to three stereogenic centers in a single operation...
  29. ncbi Bis-tetrahydrofuran: a privileged ligand for darunavir and a new generation of hiv protease inhibitors that combat drug resistance
    Arun K Ghosh
    Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
    ChemMedChem 1:939-50. 2006
  30. ncbi Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance
    Arun K Ghosh
    Department of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, USA
    J Med Chem 49:5252-61. 2006
    ..35 A resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance...
  31. ncbi Design and synthesis of novel HIV-1 protease inhibitors incorporating oxyindoles as the P2'-ligands
    Arun K Ghosh
    Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
    Bioorg Med Chem Lett 16:1869-73. 2006
    ..The effects of substituents, spirocyclic rings, and ring sizes have been investigated. A number of inhibitors exhibited low nanomolar inhibitory potencies against HIV protease...
  32. pmc Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M
    Andrey Yu Kovalevsky
    Department of Biology, Molecular Basis of Disease, Georgia State University, Atlanta, Georgia 30303, USA
    J Med Chem 49:1379-87. 2006
    ..The observed changes in PR structure and activity are discussed in relation to the potential for development of resistant mutants on exposure to TMC-114...
  33. pmc Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114
    Andrey Y Kovalevsky
    Department of Biology, Molecular Basis of Disease, GA State University, Atlanta, GA 30303, USA
    J Mol Biol 363:161-73. 2006
    ..The existence of the second binding site and two diastereomers suggest a mechanism for the high effectiveness of TMC114 on drug-resistant HIV and the potential design of new inhibitors...
  34. pmc Effect of flap mutations on structure of HIV-1 protease and inhibition by saquinavir and darunavir
    Fengling Liu
    Department of Biology, Molecular Basis of Disease Program, Georgia State University, Atlanta, GA 30303, USA
    J Mol Biol 381:102-15. 2008
    ..This analysis of structural and kinetic effects of the mutants will assist in the development of more effective inhibitors for drug-resistant HIV...
  35. pmc Potent HIV-1 protease inhibitors incorporating meso-bicyclic urethanes as P2-ligands: structure-based design, synthesis, biological evaluation and protein-ligand X-ray studies
    Arun K Ghosh
    Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA
    Org Biomol Chem 6:3703-13. 2008
    ..A protein-ligand X-ray structure of -bound HIV-1 protease revealed a number of key hydrogen bonding interactions at the S2-subsite. We have created an active model of inhibitor based upon this X-ray structure...
  36. pmc L-selectride-mediated highly diastereoselective asymmetric reductive aldol reaction: access to an important subunit for bioactive molecules
    Arun K Ghosh
    Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA
    Org Lett 10:4811-4. 2008
    ..The resulting alpha,alpha-dimethyl-beta-hydroxy ketones are inherent to a variety of biologically active natural products...
  37. pmc Structural evidence for effectiveness of darunavir and two related antiviral inhibitors against HIV-2 protease
    Andrey Y Kovalevsky
    Department of Biology, Molecular Basis of Disease Program, Georgia State University, Atlanta, GA 30303, USA
    J Mol Biol 384:178-92. 2008
    ..These near-atomic-resolution crystal structures verify the inhibitor potency for PR1 and PR2 and will provide the basis for the development of antiviral inhibitors targeting PR2...
  38. pmc Solution kinetics measurements suggest HIV-1 protease has two binding sites for darunavir and amprenavir
    Andrey Y Kovalevsky
    Departments of Biology and Chemistry, Molecular Basis of Disease Program, Georgia State University, Atlanta, Georgia 30303, USA
    J Med Chem 51:6599-603. 2008
    ..The inhibition model is consistent with the observed second binding site for darunavir and helps to explain its antiviral potency...
  39. pmc Peloruside B, a potent antitumor macrolide from the New Zealand marine sponge Mycale hentscheli: isolation, structure, total synthesis, and bioactivity
    A Jonathan Singh
    Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand
    J Org Chem 75:2-10. 2010
    ..The synthesis features Sharpless dihydroxylation, Brown's asymmetric allylboration reaction, reductive aldol coupling, Yamaguchi macrolactonization, and selective methylation...
  40. pmc Prediction of potency of protease inhibitors using free energy simulations with polarizable quantum mechanics-based ligand charges and a hybrid water model
    Debananda Das
    Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 1868, USA
    J Chem Inf Model 49:2851-62. 2009
    ....
  41. pmc Design, synthesis, protein-ligand X-ray structure, and biological evaluation of a series of novel macrocyclic human immunodeficiency virus-1 protease inhibitors to combat drug resistance
    Arun K Ghosh
    Department of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, USA
    J Med Chem 52:7689-705. 2009
    ..Protein-ligand X-ray structures of inhibitors 2 and 14c provided critical molecular insights into the ligand-binding site interactions...
  42. pmc Novel protease inhibitors (PIs) containing macrocyclic components and 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane that are potent against multi-PI-resistant HIV-1 variants in vitro
    Yasushi Tojo
    Department of Hematology, Kumamoto University School of Medicine, 1 1 1 Honjo, Kumamoto 860 8556, Japan
    Antimicrob Agents Chemother 54:3460-70. 2010
    ..The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIVmPIr...
  43. pmc An asymmetric total synthesis of brevisamide
    Arun K Ghosh
    Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, USA
    Org Lett 11:4164-7. 2009
    ..The synthesis also features a modified Wolff-Kishner reduction, Rubottom oxidation, and Suzuki-Miyaura coupling to furnish brevisamide...
  44. pmc GRL-02031, a novel nonpeptidic protease inhibitor (PI) containing a stereochemically defined fused cyclopentanyltetrahydrofuran potent against multi-PI-resistant human immunodeficiency virus type 1 in vitro
    Yasuhiro Koh
    Department of Hematology, Kumamoto University Graduate School of Medicine, Kumamoto, Japan
    Antimicrob Agents Chemother 53:997-1006. 2009
    ..The present data warrant the further development of GRL-02031 as a potential therapeutic agent for the treatment of infections with primary and multidrug-resistant HIV-1 variants...
  45. pmc Novel HIV-1 protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran, that are potent against multi-PI-resistant HIV-1 variants
    Kazuhiko Ide
    Department of Hematology, Kumamoto University School of Medicine, Kumamoto 860 8556, Japan
    Antimicrob Agents Chemother 55:1717-27. 2011
    ..The present findings warrant that GRL-1398 be further developed as a potential drug for treating individuals with HIV-1 infection...
  46. pmc Total synthesis of (-)-platensimycin, a novel antibacterial agent
    Arun K Ghosh
    Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA
    J Org Chem 74:1163-70. 2009
    ..The synthesis also featured an efficient Petasis olefination, a hydroboration sequence, a Gais's asymmetric Horner-Wadsworth-Emmons reaction, and a mercury salt catalyzed enol ether isomerization...
  47. pmc Design of HIV-1 protease inhibitors with pyrrolidinones and oxazolidinones as novel P1'-ligands to enhance backbone-binding interactions with protease: synthesis, biological evaluation, and protein-ligand X-ray studies
    Arun K Ghosh
    Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA
    J Med Chem 52:3902-14. 2009
    ....
  48. ncbi Highly diastereoselective synthesis of modified nucleosides via an asymmetric multicomponent reaction
    Arun K Ghosh
    Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA
    Chem Commun (Camb) 46:1218-20. 2010
    ..We have developed a practical synthesis of unique nucleoside derivatives via TiCl(4) promoted multicomponent reaction of optically active dihydrofuran, ethyl pyruvate/glyoxylate, and a TMS protected nucleobase in a single-pot operation...
  49. pmc The assembly-inducing laulimalide/peloruside a binding site on tubulin: molecular modeling and biochemical studies with [³H]peloruside A
    Tam Luong Nguyen
    Target Structure Based Drug Discovery Group, SAIC Frederick, Inc, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA
    J Chem Inf Model 50:2019-28. 2010
    ....
  50. pmc A stereoselective synthesis of (+)-herboxidiene/GEX1A
    Arun K Ghosh
    Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States
    Org Lett 13:66-9. 2011
    ..The synthesis of the C10-C19 segment was accomplished using Brown's crotylboration, asymmetric alkylation, and a stereoselective allylic chlorination reactions...
  51. pmc Design and synthesis of potent HIV-1 protease inhibitors incorporating hexahydrofuropyranol-derived high affinity P(2) ligands: structure-activity studies and biological evaluation
    Arun K Ghosh
    Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
    J Med Chem 54:622-34. 2011
    ..An active site model of 35a was created based upon the X-ray structure of 1b-bound HIV-1 protease. The model offers molecular insights regarding ligand-binding site interactions of the hexahydrofuropyranol-derived novel P2-ligand...
  52. pmc Enantioselective total synthesis of (-)-zampanolide, a potent microtubule-stabilizing agent
    Arun K Ghosh
    Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, USA
    Org Lett 13:4108-11. 2011
    ..The synthesis features cross-metathesis to construct the trisubstituted olefin and a ring-closing metathesis to form the macrolactone. The final N-acyl aminal formation was stereoselectively accomplished by an organocatalytic reaction...
  53. pmc In vitro selection of highly darunavir-resistant and replication-competent HIV-1 variants by using a mixture of clinical HIV-1 isolates resistant to multiple conventional protease inhibitors
    Yasuhiro Koh
    Department of Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860 8556, Japan
    J Virol 84:11961-9. 2010
    ..HIV-1(MIX(P51)) should be useful in elucidating the mechanisms of HIV-1 resistance to DRV and related agents...
  54. pmc Enantioselective syntheses of the proposed structures of cytotoxic macrolides iriomoteolide-1a and -1b
    Arun K Ghosh
    Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, USA
    Org Lett 12:3120-3. 2010
    ..The synthesis features Julia-Kocienski olefination, Sharpless asymmetric epoxidation, Brown asymmetric crotylboration, a Sakurai reaction, an aldol reaction, and enzymatic resolution as the key steps...
  55. pmc Loss of protease dimerization inhibition activity of darunavir is associated with the acquisition of resistance to darunavir by HIV-1
    Yasuhiro Koh
    Department of Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, Japan
    J Virol 85:10079-89. 2011
    ..The finding that 4 substitutions in PR are required for significant loss of DRV's protease dimerization inhibition should at least partially explain the reason DRV has a high genetic barrier against HIV's acquisition of DRV resistance...
  56. pmc Capturing the essence of organic synthesis: from bioactive natural products to designed molecules in today's medicine
    Arun K Ghosh
    Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, USA
    J Org Chem 75:7967-89. 2010
    ..This paper also highlights our approach to molecular design and synthesis of conceptually novel inhibitors against target proteins involved in the pathogenesis of human diseases, including AIDS and Alzheimer's disease...
  57. ncbi Effects of CC chemokine receptor 5 (CCR5) inhibitors on the dynamics of CCR5 and CC-chemokine-CCR5 interactions
    Hirotomo Nakata
    Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
    Antivir Ther 15:321-31. 2010
    ..This study aimed to examine how CC chemokine receptor 5 (CCR5) inhibitors (aplaviroc [APL], TAK779 and maraviroc [MVC]) interact with CCR5 and affect its dynamics and physiological CC-chemokine-CCR5 interactions...