Structure‐Based Macrocyclization of Substrate Analogue NS2B‐NS3
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NS3 Protease from Flavivirus As a Target for Designing Antiviral Inhibitors Against Dengue Virus
Genetics and Molecular Biology, 33, 2, 214-219 (2010) Copyright © 2010, Sociedade Brasileira de Genética. Printed in Brazil www.sbg.org.br Review Article NS3 protease from flavivirus as a target for designing antiviral inhibitors against dengue virus Satheesh Natarajan Department of Biochemistry, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malayasia. Abstract The development of novel therapeutic agents is essential for combating the increasing number of cases of dengue fever in endemic countries and among a large number of travelers from non-endemic countries. The dengue virus has three structural proteins and seven non-structural (NS) proteins. NS3 is a multifunctional protein with an N-terminal protease domain (NS3pro) that is responsible for proteolytic processing of the viral polyprotein, and a C-terminal region that contains an RNA triphosphatase, RNA helicase and RNA-stimulated NTPase domain that are essential for RNA replication. The serine protease domain of NS3 plays a central role in the replicative cycle of den- gue virus. This review discusses the recent structural and biological studies on the NS2B-NS3 protease-helicase and considers the prospects for the development of small molecules as antiviral drugs to target this fascinating, multifunctional protein. Key words: antiviral inhibitor, drug discovery, multifunctional protein, NS3, protease. Received: March 4, 2009; Accepted: November 1, 2009. Introduction seven non-structural proteins involved in viral replication The genus Flavivirus in the family Flaviviridae con- and maturation (Henchal and Putnak, 1990; Kautner et al., tains a large number of viral pathogens that cause severe 1996). The virus-encoded protease complex NS2B-NS3 is morbidity and mortality in humans and animals (Bancroft, responsible for cleaving the NS2A/NS2B, NS2B/NS3, 1996). -
Serine Proteases with Altered Sensitivity to Activity-Modulating
(19) & (11) EP 2 045 321 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 08.04.2009 Bulletin 2009/15 C12N 9/00 (2006.01) C12N 15/00 (2006.01) C12Q 1/37 (2006.01) (21) Application number: 09150549.5 (22) Date of filing: 26.05.2006 (84) Designated Contracting States: • Haupts, Ulrich AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 51519 Odenthal (DE) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • Coco, Wayne SK TR 50737 Köln (DE) •Tebbe, Jan (30) Priority: 27.05.2005 EP 05104543 50733 Köln (DE) • Votsmeier, Christian (62) Document number(s) of the earlier application(s) in 50259 Pulheim (DE) accordance with Art. 76 EPC: • Scheidig, Andreas 06763303.2 / 1 883 696 50823 Köln (DE) (71) Applicant: Direvo Biotech AG (74) Representative: von Kreisler Selting Werner 50829 Köln (DE) Patentanwälte P.O. Box 10 22 41 (72) Inventors: 50462 Köln (DE) • Koltermann, André 82057 Icking (DE) Remarks: • Kettling, Ulrich This application was filed on 14-01-2009 as a 81477 München (DE) divisional application to the application mentioned under INID code 62. (54) Serine proteases with altered sensitivity to activity-modulating substances (57) The present invention provides variants of ser- screening of the library in the presence of one or several ine proteases of the S1 class with altered sensitivity to activity-modulating substances, selection of variants with one or more activity-modulating substances. A method altered sensitivity to one or several activity-modulating for the generation of such proteases is disclosed, com- substances and isolation of those polynucleotide se- prising the provision of a protease library encoding poly- quences that encode for the selected variants. -
Proteolytic Enzymes in Grass Pollen and Their Relationship to Allergenic Proteins
Proteolytic Enzymes in Grass Pollen and their Relationship to Allergenic Proteins By Rohit G. Saldanha A thesis submitted in fulfilment of the requirements for the degree of Masters by Research Faculty of Medicine The University of New South Wales March 2005 TABLE OF CONTENTS TABLE OF CONTENTS 1 LIST OF FIGURES 6 LIST OF TABLES 8 LIST OF TABLES 8 ABBREVIATIONS 8 ACKNOWLEDGEMENTS 11 PUBLISHED WORK FROM THIS THESIS 12 ABSTRACT 13 1. ASTHMA AND SENSITISATION IN ALLERGIC DISEASES 14 1.1 Defining Asthma and its Clinical Presentation 14 1.2 Inflammatory Responses in Asthma 15 1.2.1 The Early Phase Response 15 1.2.2 The Late Phase Reaction 16 1.3 Effects of Airway Inflammation 16 1.3.1 Respiratory Epithelium 16 1.3.2 Airway Remodelling 17 1.4 Classification of Asthma 18 1.4.1 Extrinsic Asthma 19 1.4.2 Intrinsic Asthma 19 1.5 Prevalence of Asthma 20 1.6 Immunological Sensitisation 22 1.7 Antigen Presentation and development of T cell Responses. 22 1.8 Factors Influencing T cell Activation Responses 25 1.8.1 Co-Stimulatory Interactions 25 1.8.2 Cognate Cellular Interactions 26 1.8.3 Soluble Pro-inflammatory Factors 26 1.9 Intracellular Signalling Mechanisms Regulating T cell Differentiation 30 2 POLLEN ALLERGENS AND THEIR RELATIONSHIP TO PROTEOLYTIC ENZYMES 33 1 2.1 The Role of Pollen Allergens in Asthma 33 2.2 Environmental Factors influencing Pollen Exposure 33 2.3 Classification of Pollen Sources 35 2.3.1 Taxonomy of Pollen Sources 35 2.3.2 Cross-Reactivity between different Pollen Allergens 40 2.4 Classification of Pollen Allergens 41 2.4.1 -
Inhibition of the NS2B-NS3 Protease – Towards a Causative Therapy for Dengue Virus Diseases
Inhibition of the NS2B-NS3 Protease – Towards a Causative Therapy for Dengue Virus Diseases Gerd Katzenmeier# Laboratory of Molecular Virology, Institute of Molecular Biology and Genetics, Mahidol University, Salaya Campus, Phutthamonthon No. 4 Rd., Nakornpathom 73170, Thailand Abstract The high impact of diseases caused by dengue viruses on global health is now reflected in an increased interest in the identification of drug targets and the rationale-based development of antiviral inhibitors which are suitable for a causative treatment of severe forms of dengue virus infections – dengue haemorrhagic fever and dengue shock syndrome. A promising target for the design of specific inhibitors is the dengue virus NS3 serine protease which – in the complex with the small activator protein NS2B – catalyses processing of the viral polyprotein at a number of sites in the nonstructural region. The NS3 protease is an indispensable component of the viral replication machinery and inhibition of this protein offers the prospect of eventually preventing dengue viruses from replication and maturation. After nearly a decade of mainly genetic analysis of flaviviral replication, recent studies have contributed substantial biochemical information on polyprotein processing including the 3-dimensional structure of the dengue virus NS3 protease domain, the mechanism of co-factor-dependent activation and sensitive in vitro assays which are needed for studies on substrate specificity and the development of high-throughput assays for inhibitor screening. This review discusses recent biochemical findings which are relevant to the design of potential inhibitors directed against the dengue virus NS3 protease. Keywords: Dengue virus, NS2B/NS3, polyprotein, protease, inhibitor, treatment. Viral polyprotein processing nucleotides and encodes a single polyprotein precursor of 3,391 amino acid Dengue viruses, members of the Flaviviridae residues[3]. -
(12) United States Patent (10) Patent No.: US 8,561,811 B2 Bluchel Et Al
USOO8561811 B2 (12) United States Patent (10) Patent No.: US 8,561,811 B2 Bluchel et al. (45) Date of Patent: Oct. 22, 2013 (54) SUBSTRATE FOR IMMOBILIZING (56) References Cited FUNCTIONAL SUBSTANCES AND METHOD FOR PREPARING THE SAME U.S. PATENT DOCUMENTS 3,952,053 A 4, 1976 Brown, Jr. et al. (71) Applicants: Christian Gert Bluchel, Singapore 4.415,663 A 1 1/1983 Symon et al. (SG); Yanmei Wang, Singapore (SG) 4,576,928 A 3, 1986 Tani et al. 4.915,839 A 4, 1990 Marinaccio et al. (72) Inventors: Christian Gert Bluchel, Singapore 6,946,527 B2 9, 2005 Lemke et al. (SG); Yanmei Wang, Singapore (SG) FOREIGN PATENT DOCUMENTS (73) Assignee: Temasek Polytechnic, Singapore (SG) CN 101596422 A 12/2009 JP 2253813 A 10, 1990 (*) Notice: Subject to any disclaimer, the term of this JP 2258006 A 10, 1990 patent is extended or adjusted under 35 WO O2O2585 A2 1, 2002 U.S.C. 154(b) by 0 days. OTHER PUBLICATIONS (21) Appl. No.: 13/837,254 Inaternational Search Report for PCT/SG2011/000069 mailing date (22) Filed: Mar 15, 2013 of Apr. 12, 2011. Suen, Shing-Yi, et al. “Comparison of Ligand Density and Protein (65) Prior Publication Data Adsorption on Dye Affinity Membranes Using Difference Spacer Arms'. Separation Science and Technology, 35:1 (2000), pp. 69-87. US 2013/0210111A1 Aug. 15, 2013 Related U.S. Application Data Primary Examiner — Chester Barry (62) Division of application No. 13/580,055, filed as (74) Attorney, Agent, or Firm — Cantor Colburn LLP application No. -
Peptide Sequence
Peptide Sequence Annotation AADHDG CAS-L1 AAEAISDA M10.005-stromelysin 1 (MMP-3) AAEHDG CAS-L2 AAEYGAEA A01.009-cathepsin D AAGAMFLE M10.007-stromelysin 3 (MMP-11) AAQNASMW A06.001-nodavirus endopeptidase AASGFASP M04.003-vibriolysin ADAHDG CAS-L3 ADAPKGGG M02.006-angiotensin-converting enzyme 2 ADATDG CAS-L5 ADAVMDNP A01.009-cathepsin D ADDPDG CAS-21 ADEPDG CAS-L11 ADETDG CAS-22 ADEVDG CAS-23 ADGKKPSS S01.233-plasmin AEALERMF A01.009-cathepsin D AEEQGVTD C03.007-rhinovirus picornain 3C AETFYVDG A02.001-HIV-1 retropepsin AETWYIDG A02.007-feline immunodeficiency virus retropepsin AFAHDG CAS-L24 AFATDG CAS-25 AFDHDG CAS-L26 AFDTDG CAS-27 AFEHDG CAS-28 AFETDG CAS-29 AFGHDG CAS-30 AFGTDG CAS-31 AFQHDG CAS-32 AFQTDG CAS-33 AFSHDG CAS-L34 AFSTDG CAS-35 AFTHDG CAS-L36 AGERGFFY Insulin B-chain AGLQRGGG M14.004-carboxypeptidase N AGSHLVEA Insulin B-chain AIDIDG CAS-L37 AIDPDG CAS-38 AIDTDG CAS-39 AIDVDG CAS-L40 AIEHDG CAS-L41 AIEIDG CAS-L42 AIENDG CAS-43 AIEPDG CAS-44 AIEQDG CAS-45 AIESDG CAS-46 AIETDG CAS-47 AIEVDG CAS-48 AIFQGPID C03.007-rhinovirus picornain 3C AIGHDG CAS-49 AIGNDG CAS-L50 AIGPDG CAS-L51 AIGQDG CAS-52 AIGSDG CAS-53 AIGTDG CAS-54 AIPMSIPP M10.051-serralysin AISHDG CAS-L55 AISNDG CAS-L56 AISPDG CAS-57 AISQDG CAS-58 AISSDG CAS-59 AISTDG CAS-L60 AKQRAKRD S08.071-furin AKRQGLPV C03.007-rhinovirus picornain 3C AKRRAKRD S08.071-furin AKRRTKRD S08.071-furin ALAALAKK M11.001-gametolysin ALDIDG CAS-L61 ALDPDG CAS-62 ALDTDG CAS-63 ALDVDG CAS-L64 ALEIDG CAS-L65 ALEPDG CAS-L66 ALETDG CAS-67 ALEVDG CAS-68 ALFQGPLQ C03.001-poliovirus-type picornain -
(12) United States Patent (10) Patent No.: US 9,636,359 B2 Kenyon Et Al
USOO9636359B2 (12) United States Patent (10) Patent No.: US 9,636,359 B2 Kenyon et al. (45) Date of Patent: May 2, 2017 (54) PHARMACEUTICAL COMPOSITION FOR (52) U.S. Cl. TREATING CANCER COMPRISING CPC ............ A61K 33/04 (2013.01); A61 K3I/095 TRYPSINOGEN AND/OR (2013.01); A61K 3L/21 (2013.01); A61K 38/47 CHYMOTRYPSINOGEN AND AN ACTIVE (2013.01); A61K 38/4826 (2013.01); A61 K AGENT SELECTED FROMA SELENUM 45/06 (2013.01) (58) Field of Classification Search COMPOUND, A VANILLOID COMPOUND None AND A CYTOPLASMC GLYCOLYSIS See application file for complete search history. REDUCTION AGENT (75) Inventors: Julian Norman Kenyon, Hampshire (56) References Cited (GB); Paul Rodney Clayton, Surrey U.S. PATENT DOCUMENTS (GB); David Tosh, Bath and North East Somerset (GB); Fernando Felguer, 4,514,388 A * 4, 1985 Psaledakis ................... 424/94.1 Glenside (AU); Ralf Brandt, Greenwith 4,978.332 A * 12/1990 Luck ...................... A61K 33,24 (AU) 514,930 (Continued) (73) Assignee: The University of Sydney, New South Wales (AU) FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this KR 2007/0012040 1, 2007 patent is extended or adjusted under 35 WO WO 2009/061051 ck 5, 2009 U.S.C. 154(b) by 0 days. (21) Appl. No.: 13/502,917 OTHER PUBLICATIONS (22) PCT Fed: Oct. 22, 2010 Novak JF et al. Proenzyme Therapy of Cancer, Anticanc Res 25: 1157-1178, 2005).* (86) PCT No.: PCT/AU2O1 O/OO1403 (Continued) S 371 (c)(1), (2), (4) Date: Jun. 22, 2012 Primary Examiner — Erin M Bowers (74) Attorney, Agent, or Firm — Carol L. -
(12) Patent Application Publication (10) Pub. No.: US 2015/0240226A1 Mathur Et Al
US 20150240226A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0240226A1 Mathur et al. (43) Pub. Date: Aug. 27, 2015 (54) NUCLEICACIDS AND PROTEINS AND CI2N 9/16 (2006.01) METHODS FOR MAKING AND USING THEMI CI2N 9/02 (2006.01) CI2N 9/78 (2006.01) (71) Applicant: BP Corporation North America Inc., CI2N 9/12 (2006.01) Naperville, IL (US) CI2N 9/24 (2006.01) CI2O 1/02 (2006.01) (72) Inventors: Eric J. Mathur, San Diego, CA (US); CI2N 9/42 (2006.01) Cathy Chang, San Marcos, CA (US) (52) U.S. Cl. CPC. CI2N 9/88 (2013.01); C12O 1/02 (2013.01); (21) Appl. No.: 14/630,006 CI2O I/04 (2013.01): CI2N 9/80 (2013.01); CI2N 9/241.1 (2013.01); C12N 9/0065 (22) Filed: Feb. 24, 2015 (2013.01); C12N 9/2437 (2013.01); C12N 9/14 Related U.S. Application Data (2013.01); C12N 9/16 (2013.01); C12N 9/0061 (2013.01); C12N 9/78 (2013.01); C12N 9/0071 (62) Division of application No. 13/400,365, filed on Feb. (2013.01); C12N 9/1241 (2013.01): CI2N 20, 2012, now Pat. No. 8,962,800, which is a division 9/2482 (2013.01); C07K 2/00 (2013.01); C12Y of application No. 1 1/817,403, filed on May 7, 2008, 305/01004 (2013.01); C12Y 1 1 1/01016 now Pat. No. 8,119,385, filed as application No. PCT/ (2013.01); C12Y302/01004 (2013.01); C12Y US2006/007642 on Mar. 3, 2006. -
Peptidases: a View of Classification and Nomenclature
Proteases: New Perspectives V. Turk (ed.) © 1999 Birkhauser Verlag Basel/Switzerland Peptidases: a view of classification and nomenclature Alan 1. Barrett MRC Molecular Enzymology Laboratory, The Babraham Institute, Cambridge CB2 4AT, UK Introduction It is beyond question that the results of research on proteolytic enzymes, or peptidases, are already benefiting mankind in many ways, and there is no doubt that research in this area has the potential to contribute still more in the future. One of the clearest indications of the gener al recognition of this promise is the vast annual expenditure of the pharmaceutical industry on exploring the involvement of peptidases in human health and disease. The high and accelerating rate of research on peptidases is being rewarded by a rate of dis covery that could not have been imagined just a few years ago. One measure of this is the num ber of known peptidases. At the present time, we can recognise perhaps 600 distinct peptidas es, including over 200 that are expressed in mammals, and new ones are being discovered almost daily. This means that there is a clear need for sound systems for classifying the enzymes and for naming them. Only with such systems in place can the wealth of new information that is becoming available be shared efficiently amongst the many scientists now active in this field of research. Without such systems, there will be needless and expensive duplication of effort, and the rate of discovery, and its consequent benefits to mankind, will be slower. The justifi cation for trying to improve the systems is therefore strictly practical, and most of the questions that arise are best dealt with by asking what will be most useful to the scientists working in the field, not by reference to any abstract theory. -
Springer Handbook of Enzymes
Dietmar Schomburg Ida Schomburg (Eds.) Springer Handbook of Enzymes Alphabetical Name Index 1 23 © Springer-Verlag Berlin Heidelberg New York 2010 This work is subject to copyright. All rights reserved, whether in whole or part of the material con- cerned, specifically the right of translation, printing and reprinting, reproduction and storage in data- bases. The publisher cannot assume any legal responsibility for given data. Commercial distribution is only permitted with the publishers written consent. Springer Handbook of Enzymes, Vols. 1–39 + Supplements 1–7, Name Index 2.4.1.60 abequosyltransferase, Vol. 31, p. 468 2.7.1.157 N-acetylgalactosamine kinase, Vol. S2, p. 268 4.2.3.18 abietadiene synthase, Vol. S7,p.276 3.1.6.12 N-acetylgalactosamine-4-sulfatase, Vol. 11, p. 300 1.14.13.93 (+)-abscisic acid 8’-hydroxylase, Vol. S1, p. 602 3.1.6.4 N-acetylgalactosamine-6-sulfatase, Vol. 11, p. 267 1.2.3.14 abscisic-aldehyde oxidase, Vol. S1, p. 176 3.2.1.49 a-N-acetylgalactosaminidase, Vol. 13,p.10 1.2.1.10 acetaldehyde dehydrogenase (acetylating), Vol. 20, 3.2.1.53 b-N-acetylgalactosaminidase, Vol. 13,p.91 p. 115 2.4.99.3 a-N-acetylgalactosaminide a-2,6-sialyltransferase, 3.5.1.63 4-acetamidobutyrate deacetylase, Vol. 14,p.528 Vol. 33,p.335 3.5.1.51 4-acetamidobutyryl-CoA deacetylase, Vol. 14, 2.4.1.147 acetylgalactosaminyl-O-glycosyl-glycoprotein b- p. 482 1,3-N-acetylglucosaminyltransferase, Vol. 32, 3.5.1.29 2-(acetamidomethylene)succinate hydrolase, p. 287 Vol. -
Project Number: MQP-BC-DSA-0639 RECOMBINANT CLONING AND
Project Number: MQP-BC-DSA-0639 RECOMBINANT CLONING AND EXPRESSION OF VIRAL PROTEINS FROM WEST NILE AND DENGUE VIRUSES A Major Qualifying Project Report Submitted to the Faculty of the WORCESTER POLYTECHNIC INSTITUTE in partial fulfillment of the requirements for the Degree of Bachelor of Science in Biochemistry By Sheila Ginés April 28, 2005 APPROVED: Irene Bosch, Ph.D. Dave Adams, Ph.D. Center for Infectious Diseases WPI Project Advisor UMass Medical Center Major Advisor ABSTRACT Recent studies with Dengue (DEN) and West Nile (WN) viruses have focused on structural analyses, and host cellular and immunological responses to viral infection. In this project, various DEN and WN proteins were expressed in E. coli using recombinant expression plasmids. Expression was verified by RT-PCR and immunoblots. The expressed proteins will be used in the future to test T-cell reactivities against viral proteins. 2 TABLE OF CONTENTS Signature Page ………………………………………………………………. 1 Abstract ……………………………………………………………………... 2 Table of Contents ………………………………………………………….... 3 Acknowledgements …………………………………………………………. 4 Background …………………………………………………………………. 5 Project Purpose …………………………………………………………...… 19 Methods …………………………………………….…………….………… 20 Results ……………………………………………………………………… 28 Discussion ………………………………………………………………….. 36 Bibliography ………………………………………………………………... 38 Appendix 1- West Nile Genome Sequence .………………………………... 40 Appendix 2- Dengue Genome Sequence ….………………………………... 44 Appendix 3- QIAGEN QIAquick Gel Extraction Protocol ….……………... 48 Appendix 4- QIAGEN QIAquick Miniprep Protocol …………………..…... 49 3 ACKNOWLEDGMENTS I owe the privilege of working at the Center of Infectious Diseases and Vaccine Research (CIDVR) in the University of Massachusetts Medical School (Worcester, MA) to Dr. Alan Rothman and Dr. Irene Bosch. I am appreciative of Kris Giaya and Rajas Warke for taking their time to instruct and direct me in the lab. In addition, all the researchers at CIDVR were generous and helpful with their time, knowledge, workspace, and materials. -
Potential Inhibitors of Dengue and West Nile Virus Proteases
POTENTIAL INHIBITORS OF DENGUE AND WEST NILE VIRUS PROTEASES A Thesis By Swathi Mohan Master of Science University of Madras, 2001 Bachelor of Science Osmania University, 1999 Submitted to the Department of Chemistry and the faculty of the Graduate School of Wichita State University in partial fulfillment of the requirement for the degree of Master of Science July 2006 POTENTIAL INHIBITORS OF DENGUE AND WEST NILE VIRUS PROTEASES I have examined the final copy of this thesis for form and content and recommend that it be accepted in partial fulfillment of the requirement for the degree of Master of Science with a major in Chemistry ___________________________________ William C. Groutas, Committee Chair We have read this thesis and recommend its acceptance ___________________________________ Erach R. Talaty, Committee Member ___________________________________ Michael Van Stipdonk, Committee Member ___________________________________ Lop-Hing Ho, Committee Member ii ACKNOWLEDGEMENTS I would like to express my deep sense of gratitude to my Research Advisor, Dr. Groutas for giving me an opportunity to work in his research group and for his guidance and support through these years. Dr. Groutas, thank you so much for having taught me all about chemistry and life. You have been a tremendous guiding force to me and you have made my graduate education at Wichita State University a memory of pleasure. I would all like to thank my committee members, Dr. Talaty, Dr. Stipdonk, and Dr. Ho for their advice and helpful suggestions. I have had great pleasure in working with my fellow group members for these years and I would like to express my appreciation for all the help they have given me apart from their valuable friendships.