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035 a| (Sirsi) o1144494827;

035 a| (OCoLC)1144494827;

049 a| EREE;

100 1 a| Rohlik, Denise,e| author.?| UNAUTHORIZED;

245 10 a| Development of small-molecule inhibitors of the initiating proteases, C1r and C1s, of the classical complement pathway /c| by Denise Rohlik.;

264 1 a| [Greenville, N.C.] :b| [East Carolina University],c| 2019.;

300 a| 101 pages :b| color illustrations.;

336 a| textb| txt2| rdacontent;

337 a| computerb| c2| rdamedia;

338 a| online resourceb| cr2| rdacarrier;

347 a| text fileb| PDFc| 3.346 MB2| rda;

490 1 a| ECU Brody School of Medicine thesis;

538 a| System requirements: Adobe Reader.;

538 a| Mode of access: World Wide Web.;

502 b| M.S.c| East Carolina Universityd| 2019.;

500 a| Presented to the faculty of the Biomedical Sciences Program;

500 a| Advisor: Brandon L. Garcia;

500 a| Title from PDF t.p. (viewed May 20, 2020).;

520 3 a| Complement is a proteolytic cascade that upon activation plays a key effector role in the innate immune system and acts to prime the adaptive immune response. During normal homeostatic events, complement is tightly regulated for its roles in immune complex clearance, lysis of target cells, opsonization, and recruitment of leukocytes and monocytes to target areas. Several endogenous regulators are responsible for the control of complement activation, however when dysregulation occurs, aberrant complement activation has been linked to autoimmune, proinflammatory, and neurodegenerative diseases, including Alzheimer's disease. Inhibition of the classical complement component C1 may ameliorate hallmarks of autoimmune and inflammatory disease. The serine proteases within the C1 complex, C1r and C1s, are promising therapeutic targets for structure-based small-molecule drug development. We investigated the activity of a series of small-molecule compounds identified in a large-scale fragment library screen and those from a cheminformatics computational docking screen in which hit compounds were predicted to bind the C1r or C1s proteases. Using surface plasmon resonance and ELISA-based assays for hit validation, we analyzed the binding affinities and the inhibitory IC50's of several compounds predicted to bind and inhibit the activation of C1r or C1s in a dose-dependent manner. In this study, we have identified four lead compounds (cmp-1611, cmp-1663, cmp-1696, cmp-1827) and their 10 active structural analogues that target and inhibit C1r activation. Given their abilities to bind and inhibit C1r and favorable physicochemical properties, our lead compounds may provide a starting point for optimizing affinity and specificity necessary for developing novel routes of therapeutic upstream complement inhibition.;

504 a| Includes bibliographical references.;

650 2 a| Complement Pathway, Classical.=| ^A1407798;

650 2 a| Peptide Hydrolases.=| ^A951829;

650 2 a| Endopeptidases.=| ^A1407818;

650 2 a| Complement C1r.=| ^A1407827;

653 a| small-molecule inhibitor;

653 a| C1s;

700 1 a| Garcia, Brandon L.,e| degree supervisor.?| UNAUTHORIZED;

710 2 a| East Carolina University.b| Department of Microbiology and Immunology.?| UNAUTHORIZED;

830 0 a| ECU Brody School of Medicine thesis.=| ^A964744;

856 40 z| Access via ScholarShipu| http://hdl.handle.net/10342/7590;

949 o| wjh;

994 a| C0b| ERE;

096 a| QW 680;

596 a| 1 4;

998 a| 5266628;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 5266628-1001l| JNETm| JOYNERr| Ys| Yt| JNE3ETDu| 3/13/2020x| ETDz| JERESOURCE;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 5266628-2001l| HSLELECm| HSLr| Ys| Yt| HEETDu| 3/13/2020x| ETDz| HERESOURCE;

Development of small-molecule inhibitors of the initiating proteases, C1r and C1s, of the classical complement pathway / by Denise Rohlik.

Author/creator	Rohlik, Denise author.
Other author	Garcia, Brandon L., degree supervisor.
Other author	East Carolina University. Department of Microbiology and Immunology.
Format	Theses and dissertations
Publication	[Greenville, N.C.] : [East Carolina University], 2019.
Description	101 pages : color illustrations.
Supplemental Content	Access via ScholarShip
Subjects	Complement Pathway, Classical. Peptide Hydrolases. Endopeptidases. Complement C1r.

Series	ECU Brody School of Medicine thesis ECU Brody School of Medicine thesis. ^A964744
Summary	Complement is a proteolytic cascade that upon activation plays a key effector role in the innate immune system and acts to prime the adaptive immune response. During normal homeostatic events, complement is tightly regulated for its roles in immune complex clearance, lysis of target cells, opsonization, and recruitment of leukocytes and monocytes to target areas. Several endogenous regulators are responsible for the control of complement activation, however when dysregulation occurs, aberrant complement activation has been linked to autoimmune, proinflammatory, and neurodegenerative diseases, including Alzheimer's disease. Inhibition of the classical complement component C1 may ameliorate hallmarks of autoimmune and inflammatory disease. The serine proteases within the C1 complex, C1r and C1s, are promising therapeutic targets for structure-based small-molecule drug development. We investigated the activity of a series of small-molecule compounds identified in a large-scale fragment library screen and those from a cheminformatics computational docking screen in which hit compounds were predicted to bind the C1r or C1s proteases. Using surface plasmon resonance and ELISA-based assays for hit validation, we analyzed the binding affinities and the inhibitory IC50's of several compounds predicted to bind and inhibit the activation of C1r or C1s in a dose-dependent manner. In this study, we have identified four lead compounds (cmp-1611, cmp-1663, cmp-1696, cmp-1827) and their 10 active structural analogues that target and inhibit C1r activation. Given their abilities to bind and inhibit C1r and favorable physicochemical properties, our lead compounds may provide a starting point for optimizing affinity and specificity necessary for developing novel routes of therapeutic upstream complement inhibition.
General note	Presented to the faculty of the Biomedical Sciences Program
General note	Advisor: Brandon L. Garcia
General note	Title from PDF t.p. (viewed May 20, 2020).
Dissertation note	M.S. East Carolina University 2019.
Bibliography note	Includes bibliographical references.
Technical details	System requirements: Adobe Reader.
Technical details	Mode of access: World Wide Web.

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Development of small-molecule inhibitors of the initiating proteases, C1r and C1s, of the classical complement pathway / by Denise Rohlik.

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