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Featured researches published by Guangxiang Luo.


Journal of Virology | 2000

De Novo Initiation of RNA Synthesis by the RNA-Dependent RNA Polymerase (NS5B) of Hepatitis C Virus

Guangxiang Luo; Robert Hamatake; Danielle M. Mathis; Jason Racela; Karen Rigat; Julie A. Lemm; Richard J. Colonno

ABSTRACT Hepatitis C virus (HCV) NS5B protein possesses an RNA-dependent RNA polymerase (RdRp) activity, a major function responsible for replication of the viral RNA genome. To further characterize the RdRp activity, NS5B proteins were expressed from recombinant baculoviruses, purified to near homogeneity, and examined for their ability to synthesize RNA in vitro. As a result, a highly active NS5B RdRp (1b-42), which contains an 18-amino acid C-terminal truncation resulting from a newly created stop codon, was identified among a number of independent isolates. The RdRp activity of the truncated NS5B is comparable to the activity of the full-length protein and is 20 times higher in the presence of Mn2+ than in the presence of Mg2+. When a 384-nucleotide RNA was used as the template, two major RNA products were synthesized by 1b-42. One is a complementary RNA identical in size to the input RNA template (monomer), while the other is a hairpin dimer RNA synthesized by a “copy-back” mechanism. Substantial evidence derived from several experiments demonstrated that the RNA monomer was synthesized through de novo initiation by NS5B rather than by a terminal transferase activity. Synthesis of the RNA monomer requires all four ribonucleotides. The RNA monomer product was verified to be the result of de novo RNA synthesis, as two expected RNA products were generated from monomer RNA by RNase H digestion. In addition, modification of the RNA template by the addition of the chain terminator cordycepin at the 3′ end did not affect synthesis of the RNA monomer but eliminated synthesis of the self-priming hairpin dimer RNA. Moreover, synthesis of RNA on poly(C) and poly(U) homopolymer templates by 1b-42 NS5B did not require the oligonucleotide primer at high concentrations (≥50 μM) of GTP and ATP, further supporting a de novo initiation mechanism. These findings suggest that HCV NS5B is able to initiate RNA synthesis de novo.


Antimicrobial Agents and Chemotherapy | 2004

Orally Active Fusion Inhibitor of Respiratory Syncytial Virus

Christopher Cianci; Kuo-Long Yu; Keith D. Combrink; Ny Sin; Bradley C. Pearce; Alan X. Wang; Rita L. Civiello; Stacey Voss; Guangxiang Luo; Kathy Kadow; Eugene V. Genovesi; Brian Lee Venables; Hatice Belgin Gulgeze; Ashok K. Trehan; Jennifer James; Lucinda Lamb; Ivette Medina; Julia Roach; Zheng Yang; Lisa Zadjura; Richard J. Colonno; Junius M. Clark; Nicholas A. Meanwell; Mark Krystal

ABSTRACT BMS-433771 was found to be a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. It exhibited excellent potency against multiple laboratory and clinical isolates of both group A and B viruses, with an average 50% effective concentration of 20 nM. Mechanism-of-action studies demonstrated that BMS-433771 inhibits the fusion of lipid membranes during both the early virus entry stage and late-stage syncytium formation. After isolation of resistant viruses, resistance was mapped to a series of single amino acid mutations in the F1 subunit of the fusion protein. Upon oral administration, BMS-433771 was able to reduce viral titers in the lungs of mice infected with RSV. This new class of orally active RSV fusion inhibitors offers potential for clinical development.


Bioorganic & Medicinal Chemistry Letters | 2002

Structure-activity relationships for a series of thiobenzamide influenza fusion inhibitors derived from 1,3,3-trimethyl-5-hydroxy-cyclohexylmethylamine.

Kuo-Long Yu; Albert Torri; Guangxiang Luo; Christopher Cianci; Katharine A. Grant-Young; Stephanie Danetz; Lawrence Tiley; Mark Krystal; Nicholas A. Meanwell

The anti-influenza activity of a series of thiobenzamide fusion inhibitors derived from 1,3,3-trimethyl-5-hydroxy-cyclohexylmethylamine is profiled. Axial disposition of the thioamide moiety is essential for potent influenza inhibitory activity.


Bioorganic & Medicinal Chemistry Letters | 2001

An approach to the identification of potent inhibitors of influenza virus fusion using parallel synthesis methodology

Milind Deshpande; Jianmei Wei; Guangxiang Luo; Christopher Cianci; Stephanie Danetz; A. Torri; Laurence Tiley; Mark Krystal; Kuo-Long Yu; Stella Huang; Qi Gao; Nicholas A. Meanwell

Structure-activity studies associated with the salicylic acid-derived inhibitor of influenza fusion, BMY-27709, were examined using a parallel synthesis approach. This SAR survey led to the discovery of potent influenza inhibitory activity in a series of aromatic amides and thioamides derived from 1,3,3-trimethyl-5-hydroxycyclohexylmethylamine. Select compounds were characterized as inhibitors of the H1 subtype of influenza A viruses that act by preventing the pH-induced fusion process, thereby blocking viral entry into host cells. In a plaque-reduction assay, the most potent inhibitors displayed EC(50) values of 0.02-0.14 microg/mL.


Bioorganic & Medicinal Chemistry Letters | 2000

Salicylamide inhibitors of influenza virus fusion

Keith D. Combrink; H. Belgin Gulgeze; Kuo-Long Yu; Bradley C. Pearce; Ashok K. Trehan; Jianmei Wei; Milind Deshpande; Mark Krystal; Albert Torri; Guangxiang Luo; Christopher Cianci; Stephanie Danetz; Laurence Tiley; Nicholas A. Meanwell

Structural variation of the quinolizidine heterocycle of the influenza fusion inhibitor BMY-27709 was examined by several topological dissections in order to illuminate the critical features of the ring system. This exercise resulted in the identification of a series of synthetically more accessible decahydroquinolines that retained the structural elements of BMY-27709 important for antiviral activity. The 2-methyl-cis-decahydroquinoline 6f was the most potent influenza inhibitor identified that demonstrated an EC50 of 90 ng/mL in a plaque reduction assay.


Bioorganic & Medicinal Chemistry Letters | 1999

Novel quinolizidine salicylamide influenza fusion inhibitors

Kuo-Long Yu; Edward H. Ruediger; Guangxiang Luo; Christopher Cianci; Stephanie Danetz; Laurence Tiley; Ashok K. Trehan; Ivo Monkovic; Bradley C. Pearce; Alain Martel; Mark Krystal; Nicholas A. Meanwell

A novel series of quinolizidine salicylamides was synthesized as specific inhibitors of the H1 subtype of influenza A viruses. These inhibitors inhibit the pH-induced fusion process, thereby blocking viral entry into host cells. Compound 16 was the most active inhibitor in this series with an EC50 of 0.25 microg/mL in plaque reduction assay. The synthesis and the SAR of these compounds are discussed.


Journal of Virology | 1997

MOLECULAR MECHANISM UNDERLYING THE ACTION OF A NOVEL FUSION INHIBITOR OF INFLUENZA A VIRUS

Guangxiang Luo; A. Torri; William E. Harte; Stephanie Danetz; Christopher Cianci; Laurence Tiley; Susan H. Day; David Mullaney; Kuo Long Yu; Carl Ouellet; Pierre Dextraze; Nicholas A. Meanwell; Richard J. Colonno; Mark Krystal


Virology | 1996

Characterization of a Hemagglutinin-Specific Inhibitor of Influenza A Virus

Guangxiang Luo; Richard J. Colonno; Mark Krystal


Journal of Virology | 1996

Characterization of inhibition of M2 ion channel activity by BL-1743, an inhibitor of influenza A virus.

Qiang Tu; Lawrence H. Pinto; Guangxiang Luo; Margaret A. Shaughnessy; David Mullaney; Stephen E. Kurtz; Mark Krystal; Robert A. Lamb


Virology | 1999

Cellular Proteins Bind to the Poly(U) Tract of the 3′ Untranslated Region of Hepatitis C Virus RNA Genome

Guangxiang Luo

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A. Torri

Bristol-Myers Squibb

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Qi Gao

Bristol-Myers Squibb

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