Zhuyan Guo

Publications (21)73.59 Total impact

• Article: 2-(2-Aminothiazol-4-yl)pyrrolidine-based tartrate diamides as potent, selective and orally bioavailable TACE inhibitors.

  Chaoyang Dai, Dansu Li, Janeta Popovici-Muller, Lianyun Zhao, Vinay M Girijavallabhan, Kristin E Rosner, Brian J Lavey, Razia Rizvi, Bandarpalle B Shankar, Michael K C Wong, [......], Peter Orth, Corey O Strickland, Jing Sun, Xiaoda Niu, Shiying Chen, Joseph A Kozlowski, Daniel J Lundell, John J Piwinski, Neng-Yang Shih, M Arshad Siddiqui
  [show abstract] [hide abstract]
  ABSTRACT: TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.
  Bioorganic & medicinal chemistry letters 01/2011; 21(10):3172-6. · 2.65 Impact Factor
• Article: Novel TNF-α converting enzyme (TACE) inhibitors as potential treatment for inflammatory diseases.

  Vinay M Girijavallabhan, Lei Chen, Chaoyang Dai, Robert J Feltz, Luke Firmansjah, Dansu Li, Seong Heon Kim, Joseph A Kozlowski, Brian J Lavey, Aneta Kosinski, [......], Guowei Zhou, Zhuyan Guo, Peter Orth, Vincent Madison, Hong Bian, Daniel Lundell, Xiaoda Niu, Himanshu Shah, Jing Sun, Shelby Umland
  [show abstract] [hide abstract]
  ABSTRACT: Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.
  Bioorganic & medicinal chemistry letters 12/2010; 20(24):7283-7. · 2.65 Impact Factor
• Article: Biaryl substituted hydantoin compounds as TACE inhibitors.

  Wensheng Yu, Ling Tong, Seong Heon Kim, Michael K C Wong, Lei Chen, De-Yi Yang, Bandarpalle B Shankar, Brian J Lavey, Guowei Zhou, Aneta Kosinski, [......], Neng-Yang Shih, M Arshad Siddiqui, Zhuyan Guo, Peter Orth, Himanshu Shah, Jing Sun, Shelby Umland, Daniel J Lundell, Xiaoda Niu, Joseph A Kozlowski
  [show abstract] [hide abstract]
  ABSTRACT: We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.
  Bioorganic & medicinal chemistry letters 09/2010; 20(17):5286-9. · 2.65 Impact Factor
• Article: Structure and activity relationships of tartrate-based TACE inhibitors.

  Dansu Li, Janeta Popovici-Muller, David B Belanger, John Caldwell, Chaoyang Dai, Maria David, Vinay M Girijavallabhan, Brian J Lavey, Joe F Lee, Zhidan Liu, [......], Shiying Chen, Joseph A Kozlowski, Daniel J Lundell, Vincent Madison, Brian McKittrick, John J Piwinski, Neng-Yang Shih, Gerald W Shipps, M Arshad Siddiqui, Corey O Strickland
  [show abstract] [hide abstract]
  ABSTRACT: The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.
  Bioorganic & medicinal chemistry letters 08/2010; 20(16):4812-5. · 2.65 Impact Factor
• Article: Discovery and SAR of hydantoin TACE inhibitors.

  Wensheng Yu, Zhuyan Guo, Peter Orth, Vincent Madison, Lei Chen, Chaoyang Dai, Robert J Feltz, Vinay M Girijavallabhan, Seong Heon Kim, Joseph A Kozlowski, [......], Kristin E Rosner, Bandarpalle B Shankar, Neng-Yang Shih, M Arshad Siddiqui, Jing Sun, Ling Tong, Shelby Umland, Michael K C Wong, De-yi Yang, Guowei Zhou
  [show abstract] [hide abstract]
  ABSTRACT: We disclose inhibitors of TNF-alpha converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.
  Bioorganic & medicinal chemistry letters 02/2010; 20(6):1877-80. · 2.65 Impact Factor
• Article: The introduction of P4 substituted 1-methylcyclohexyl groups into Boceprevir: a change in direction in the search for a second generation HCV NS3 protease inhibitor.

  Frank Bennett, Yuhua Huang, Siska Hendrata, Raymond Lovey, Stephane L Bogen, Weidong Pan, Zhuyan Guo, Andrew Prongay, Kevin X Chen, Ashok Arasappan, Srikanth Venkatraman, Francisco Velazquez, Latha Nair, Mousumi Sannigrahi, Xiao Tong, John Pichardo, Kuo-Chi Cheng, Viyyoor M Girijavallabhan, Anil K Saksena, F George Njoroge
  [show abstract] [hide abstract]
  ABSTRACT: In the search for a second generation HCV protease inhibitor, molecular modeling studies of the X-ray crystal structure of Boceprevir1 bound to the NS3 protein suggest that expansion into the S4 pocket could provide additional hydrophobic Van der Waals interactions. Effective replacement of the P4 tert-butyl with a cyclohexylmethyl ligand led to inhibitor 2 with improved enzyme and replicon activities. Subsequent modeling and SAR studies led to the pyridine 38 and sulfone analogues 52 and 53 with vastly improved PK parameters in monkeys, forming a new foundation for further exploration.
  Bioorganic & medicinal chemistry letters 02/2010; 20(8):2617-21. · 2.65 Impact Factor
• Article: Towards the second generation of Boceprevir: Dithianes as an alternative P2 substituent for 2,2-dimethyl cycloproyl proline in HCV NS3 protease inhibitors.

  Latha G Nair, Stephane Bogen, Sumei Ruan, Weidong Pan, Russel Pike, Xiao Tong, Kuo-Chi Cheng, Zhuyan Guo, Ronald J Doll, F George Njoroge
  [show abstract] [hide abstract]
  ABSTRACT: Hepatitis C (HCV) infection is a global health crisis leading to chronic liver disease. In our efforts towards a second generation HCV NS3 serine protease inhibitor with improved profile, we have undertaken SAR studies in various regions of Boceprevir including P2. Herein, we report the synthesis and structure-activity relationship studies of inhibitors with (S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid 2 as P2 substituent replacing the (1R,2S,5S)-6,6-dimethyl 3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The systematic investigation led to the discovery of highly potent inhibitor 25 (K(i)( *)=7nM, EC(90)=30nM) with improved rat exposure of 2.56microM h.
  Bioorganic & medicinal chemistry letters 01/2010; 20(5):1689-92. · 2.65 Impact Factor
• Article: Discovery of potent sulfonamide P4-capped ketoamide second generation inhibitors of hepatitis C virus NS3 serine protease with favorable pharmacokinetic profiles in preclinical species.

  Stéphane L Bogen, Ashok Arasappan, Francisco Velazquez, Melissa Blackman, Regina Huelgas, Weidong Pan, Elise Siegel, Latha G Nair, Srikanth Venkatraman, Zhuyan Guo, Ronald Doll, Neng-Yang Shih, F George Njoroge
  [show abstract] [hide abstract]
  ABSTRACT: Hepatitis is a disease characterized by inflammation of the liver, usually producing swelling and, in many cases, permanent damage to liver tissues. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically 3% of the world's population. Boceprevir, SCH 503034, (1) our first generation HCV inhibitor, has already established proof-of- concept and is currently in late stage (phase III) clinical trials. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P(4) pocket by introducing a new sulfonamide moiety and optimization of the P1/P(1)' capping led to the discovery of a novel series of inhibitors of the HCV NS3 serine protease. Optimization of the P(1) residue significantly improved potency and selectivity. The combination of optimal moieties led to the discovery of compound 47 which, in addition to being a potent inhibitor of HCV subgenomic RNA replication, was also found to have good PK profile in rat, dog and monkey.
  Bioorganic & medicinal chemistry 01/2010; 18(5):1854-65. · 2.82 Impact Factor
• Article: The discovery of novel tartrate-based TNF-alpha converting enzyme (TACE) inhibitors.

  Kristin E Rosner, Zhuyan Guo, Peter Orth, Gerald W Shipps, David B Belanger, Tin Yau Chan, Patrick J Curran, Chaoyang Dai, Yongqi Deng, Vinay M Girijavallabhan, [......], Xiaoda Niu, Jing Sun, Joseph A Kozlowski, Daniel J Lundell, Vincent Madison, Brian McKittrick, John J Piwinski, Neng-Yang Shih, M Arshad Siddiqui, Corey O Strickland
  [show abstract] [hide abstract]
  ABSTRACT: A novel series of TNF-alpha convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are bis-amides of L-tartaric acid (tartrate) and coordinate to the active site zinc in a tridentate manner. They are selective for TACE over other MMP's. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.
  Bioorganic & medicinal chemistry letters 12/2009; 20(3):1189-93. · 2.65 Impact Factor
• Article: Toward the back-up of boceprevir (SCH 503034): discovery of new extended P4-capped ketoamide inhibitors of hepatitis C virus NS3 serine protease with improved potency and pharmacokinetic profiles.

  Stéphane L Bogen, Weidong Pan, Sumei Ruan, Latha G Nair, Ashok Arasappan, Frank Bennett, Kevin X Chen, Edwin Jao, Srikanth Venkatraman, Bancha Vibulbhan, Rong Liu, Kuo-Chi Cheng, Zhuyan Guo, Xiao Tong, Anil K Saksena, Viyyoor Girijavallabhan, F George Njoroge
  [show abstract] [hide abstract]
  ABSTRACT: Hepatitis C is the most prevalent liver disease. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically an estimated 300 million people worldwide. Results of Phase I clinical studies with our first generation HCV inhibitor Boceprevir, SCH 503034 (1), presented at the 56th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) were encouraging, and thus, additional human clinical studies are underway. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P(4) pocket and optimization of the P(1)' capping led to the discovery of new ketoamide inhibitors of the HCV NS3 serine protease with improved in vitro potency. In addition to being potent inhibitors of HCV subgenomic RNA replication, some of the new P(4)-capped inhibitors were also found to have improved PK profile.
  Journal of Medicinal Chemistry 06/2009; 52(12):3679-88. · 4.80 Impact Factor
• Source

  Available from: PubMed Central

  Article: Identification of HCV protease inhibitor resistance mutations by selection pressure-based method.

  Ping Qiu, Vincent Sanfiorenzo, Stephanie Curry, Zhuyan Guo, Shaotang Liu, Angela Skelton, Ellen Xia, Constance Cullen, Robert Ralston, Jonathan Greene, Xiao Tong
  [show abstract] [hide abstract]
  ABSTRACT: A major challenge to successful antiviral therapy is the emergence of drug-resistant viruses. Recent studies have developed several automated analyses of HIV sequence polymorphism based on calculations of selection pressure (K(a)/K(s)) to predict drug resistance mutations. Similar resistance analysis programs for HCV inhibitors are not currently available. Taking advantage of the recently available sequence data of patient HCV samples from a Phase II clinical study of protease inhibitor boceprevir, we calculated the selection pressure for all codons in the HCV protease region (amino acid 1-181) to identify potential resistance mutations. The correlation between mutations was also calculated to evaluate linkage between any two mutations. Using this approach, we identified previously known major resistant mutations, including a recently reported mutation V55A. In addition, a novel mutation V158I was identified, and we further confirmed its resistance to boceprevir in protease enzyme and replicon assay. We also extended the approach to analyze potential interactions between individual mutations and identified three pairs of correlated changes. Our data suggests that selection pressure-based analysis and correlation mapping could provide useful tools to analyze large amount of sequencing data from clinical samples and to identify new drug resistance mutations as well as their linkage and correlations.
  Nucleic Acids Research 05/2009; 37(10):e74. · 8.03 Impact Factor
• Article: Discovery of novel spirocyclopropyl hydroxamate and carboxylate compounds as TACE inhibitors.

  Zhuyan Guo, Peter Orth, Shing-Chun Wong, Brian J Lavey, Neng-Yang Shih, Xiaoda Niu, Daniel J Lundell, Vincent Madison, Joseph A Kozlowski
  [show abstract] [hide abstract]
  ABSTRACT: We have discovered nanomolar inhibitors of TNF-alpha convertase (TACE) comprised of a novel spirocyclic scaffold and either a carboxylate or hydroxamate zinc binding moiety. X-ray crystal structures and computer models of selected compounds binding to TACE explain the observed SAR. We report the first TACE X-ray crystal structure for an inhibitor with a carboxylate zinc ligand.
  Bioorganic & medicinal chemistry letters 12/2008; 19(1):54-7. · 2.65 Impact Factor
• Article: Discovery of novel hydroxamates as highly potent tumor necrosis factor-alpha converting enzyme inhibitors. Part II: optimization of the S3' pocket.

  Robert D Mazzola, Zhaoning Zhu, Lisa Sinning, Brian McKittrick, Brian Lavey, James Spitler, Joseph Kozlowski, Shih Neng-Yang, Guowei Zhou, Zhuyan Guo, Peter Orth, Vincent Madison, Jing Sun, Daniel Lundell, Xiaoda Niu
  [show abstract] [hide abstract]
  ABSTRACT: A series of cyclopropyl hydroxamic acids were prepared. Many of the compounds displayed picomolar affinity for the TACE enzyme while maintaining good to excellent selectivity profiles versus MMP-1, -2, -3, -7, -14, and ADAM-10. X-ray analysis of an inhibitor in the TACE active site indicated that the molecules bound to the enzyme in the S1'-S3' pocket.
  Bioorganic & medicinal chemistry letters 10/2008; 18(21):5809-14. · 2.65 Impact Factor
• Source

  Available from: Lata Ramanathan

  Article: Key steps in the structure-based optimization of the hepatitis C virus NS3/4A protease inhibitor SCH503034.

  Vincent Madison, Andrew J Prongay, Zhuyan Guo, Nanhua Yao, John Pichardo, Thierry Fischmann, Corey Strickland, Joseph Myers, Patricia C Weber, Brian M Beyer, [......], Frank Bennett, Stephane L Bogen, Kevin Chen, Edwin Jao, Yi Tsung Liu, Raymond G Lovey, Anil K Saksena, Srikanth Venkatraman, Viyyoor Girijavallabhan, F George Njoroge
  [show abstract] [hide abstract]
  ABSTRACT: The structures of both native and S139A holo-HCV NS3/4A protease domain were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contributions to the binding energy arise from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease, which is currently in clinical trials.
  Journal of Synchrotron Radiation 06/2008; 15(Pt 3):204-7. · 2.73 Impact Factor
• Article: Discovery of novel hydroxamates as highly potent tumor necrosis factor-alpha converting enzyme inhibitors: Part I--discovery of two binding modes.

  Zhaoning Zhu, Robert Mazzola, Lisa Sinning, Brian McKittrick, Xiaoda Niu, Daniel Lundell, Jing Sun, Peter Orth, Zhuyan Guo, Vincent Madison, Richard Ingram, Brian M Beyer
  [show abstract] [hide abstract]
  ABSTRACT: Through a de novo design approach, hydroxamates derived from trans-cyclopropyl dicarboxylate were examined as potential TNF-alpha converting enzyme (TACE) inhibitors. Two distinctive series of inhibitors (A and B) were identified and shown to have different structure-activity relationship trends and selectivity profiles against other matrix metalloproteases despite their close structural similarities. X-ray crystallography of the inhibitors binding to the TACE enzyme demonstrates that each series derives its activity from the opposite enantiomer of the cyclopropyl scaffolds, which display almost superimposable hydroxamate groups that coordinate to the zinc at the catalytic site. Mode A inhibitors occupy the S1'-S3' binding pockets, whereas mode B resides in the nonprime binding sites.
  Journal of Medicinal Chemistry 03/2008; 51(4):725-36. · 5.25 Impact Factor
• Article: Characterization of resistance mutations against HCV ketoamide protease inhibitors.

  Xiao Tong, Stephane Bogen, Robert Chase, V Girijavallabhan, Zhuyan Guo, F George Njoroge, Andrew Prongay, Anil Saksena, Angela Skelton, Ellen Xia, Robert Ralston
  [show abstract] [hide abstract]
  ABSTRACT: An issue of clinical importance in the development of new antivirals for HCV is emergence of resistance. Several resistance loci to ketoamide inhibitors of the NS3/4A protease have been identified (residues V36, T54, R155, A156, and V170) by replicon and clinical studies. Using SCH 567312, a more potent protease inhibitor derived from SCH 503034 (boceprevir) series, we identified two new positions (Q41 and F43) that confer resistance to the ketoamide class. The catalytic efficiency of protease enzymes was not affected by most resistance mutations, whereas replicon fitness varied with specific mutations. SCH 503034 and another ketoamide inhibitor, VX-950 (telaprevir), showed moderate losses of activity against most resistance mutations (< or =10-fold); the highest resistance level was conferred by mutations at A156 locus. Although SCH 503034 and VX-950 bind similarly to the active site, differences in resistance level were observed with specific mutations. Changes at V36 and R155 had more severe impact on VX-950, whereas mutations at Q41, F43 and V170 conferred higher resistance to SCH 503034. Structural analysis of resistance mutations on inhibitor binding is discussed.
  Antiviral Research 03/2008; 77(3):177-85. · 4.30 Impact Factor
• Article: Discovery of the HCV NS3/4A protease inhibitor (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3- [2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II. Key steps in structure-based optimization.

  Andrew J Prongay, Zhuyan Guo, Nanhua Yao, John Pichardo, Thierry Fischmann, Corey Strickland, Joseph Myers, Patricia C Weber, Brian M Beyer, Richard Ingram, [......], Stephane L Bogen, Kevin Chen, Edwin Jao, Yi-Tsung Liu, Raymond G Lovey, Anil K Saksena, Srikanth Venkatraman, Viyyoor Girijavallabhan, F George Njoroge, Vincent Madison
  [show abstract] [hide abstract]
  ABSTRACT: The structures of both the native holo-HCV NS3/4A protease domain and the protease domain with a serine 139 to alanine (S139A) mutation were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contribution to the binding energy arises from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets [the numbering of the subsites is as defined in Berger, A.; Schechter, I. Philos. Trans. R. Soc. London, Ser. B 1970, 257, 249-264]. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease that is currently in clinical trials.
  Journal of Medicinal Chemistry 06/2007; 50(10):2310-8. · 5.25 Impact Factor
• Article: Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: a potential therapeutic agent for the treatment of hepatitis C infection.

  Srikanth Venkatraman, Stéphane L Bogen, Ashok Arasappan, Frank Bennett, Kevin Chen, Edwin Jao, Yi-Tsung Liu, Raymond Lovey, Siska Hendrata, Yuhua Huang, [......], Walter Korfmacher, Ronald White, Susan Bogdanowich-Knipp, Anastasia Pavlovsky, Prudence Bradley, Anil K Saksena, Ashit Ganguly, John Piwinski, Viyyoor Girijavallabhan, F George Njoroge
  [show abstract] [hide abstract]
  ABSTRACT: Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or polyethylene glycol (PEG)-interferon-alpha alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.
  Journal of Medicinal Chemistry 11/2006; 49(20):6074-86. · 5.25 Impact Factor
• Article: Computational Study of the Effects of Mutations A156T, D168V, and D168Q on the Binding of HCV Protease Inhibitors

  Zhuyan Guo, Andrew Prongay, Xiao Tong, Thierry Fischmann, Stephane Bogen, Francisco Velazquez, Srikanth Venkatraman, F. George Njoroge, Vincent Madison
  [show abstract] [hide abstract]
  ABSTRACT: The effect of the resistance mutations A156T, D168V, and D168Q in HCV protease on the binding of SCH 6, SCH 503034, VX-950, BILN-2061, and compound 1 was evaluated using the free energy perturbation (FEP) approach. All the inhibitors are highly potent against the wild-type enzyme, but their activity was affected differently by the mutants. A156T reduced the activity of SCH 503034, BILN-2061, and VX950 drastically (200−1000-fold) but that of SCH 6 only moderately (27-fold). SCH 503034, SCH 6, and VX-950 were not affected by either mutation D168V or D168Q, but these mutations conferred a high level of resistance to BILN-2061. Comparison of BILN-2061 with its acyclic analogue compound 1 emphasized the importance of inhibitor flexibility in overcoming drug resistance arising from the D168Q mutation. The results from FEP calculations compared well with experimental binding potencies within an error of <1 kcal/mol. Structural analysis was carried out to relate the resistance profiles to the atomic changes in the mutants.
  09/2006;
• Article: Impact of naturally occurring variants of HCV protease on the binding of different classes of protease inhibitors.

  Xiao Tong, Zhuyan Guo, Jacquelyn Wright-Minogue, Ellen Xia, Andrew Prongay, Vincent Madison, Ping Qiu, Srikanth Venkatraman, Francisco Velazquez, F George Njoroge, Bruce A Malcolm
  [show abstract] [hide abstract]
  ABSTRACT: HCV drug discovery efforts have largely focused on genotype 1 virus due to its prevalence and relatively poor response to current therapy. However, patients infected with genotype 2 and 3 viruses account for a significant number of cases and would also benefit from new therapies. In vitro studies using two chemically distinct protease inhibitors with clinical potential showed that one, VX-950, was equally active on proteases from all three genotypes, whereas the other, BILN 2061, was significantly less active on genotype 2 and 3 proteases. Naturally occurring variation near the inhibitor binding site was identified based on sequence alignment of the protease region from genotype 1-3 sequences. Substitution of amino acids in genotype 1 based on genotype 2 and 3 has revealed residues which impact binding of BILN 2061. Substitution of residues 78-80, together with 122 and 132, accounted for most of the reduced sensitivity of genotype 2. The most critical position affecting inhibitor binding to genotype 3 protease was 168. Substitution of residues at positions 168, 123, and 132 fully accounted for the reduced sensitivity of genotype 3. Comparative studies of BILN 2061 and a closely related nonmacrocycle inhibitor suggested that the rigidity of BILN 2061, while conferring greater potency against genotype 1, rendered it more sensitive to variations near the binding site. Free energy perturbation analysis confirmed the experimental observations. The identification of naturally occurring variations which can affect inhibitor binding is an important step in the design of broad-spectrum, second generation protease inhibitors.
  Biochemistry 03/2006; 45(5):1353-61. · 3.42 Impact Factor