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Viral serpin therapeutics from concept to clinic - PubMed

Review

Viral serpin therapeutics from concept to clinic

Hao Chen et al. Methods Enzymol. 2011.

Abstract

Over the past 19 years, we have developed a novel myxoma virus-derived anti-inflammatory serine protease inhibitor, termed a serpin, as a new class of immunomodulatory therapeutic. This review will describe the initial identification of viral serpins with anti-inflammatory potential, beginning with preclinical analysis of viral pathogenesis and proceeding to cell and molecular target analyses, and successful clinical trial. The central aim of this review is to describe the development of two serpins, Serp-1 and Serp-2, as a new class of immune modulating drug, from inception to implementation. We begin with an overview of the approaches used for successful mining of the virus for potential serpin immunomodulators in viruses. We then provide a methodological overview of one inflammatory animal model used to test for serpin anti-inflammatory activity followed by methods used to identify cells in the inflammatory response system targeted by these serpins and molecular responses to serpin treatment. Finally, we provide an overview of our findings from a recent, successful clinical trial of the secreted myxomaviral serpin, Serp-1, in patients with unstable inflammatory coronary arterial disease.

Copyright © 2011 Elsevier Inc. All rights reserved.

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Figures

Figure 15.1
Figure 15.1

Hypothetical models of Serp-1 (left, A) and Serp-2 (right, B) based on known crystallized homologous protein structures, PAI-1 (PBD ID: 3CVM) for Serp-1 and CrmA (PBD ID: 1C8O) for Serp-2, respectively. The arrows point to the reactive site loops (RSL).

Figure 15.2
Figure 15.2

Illustration of aortic balloon angioplasty injury in mouse model of accelerated atherosclerosis and arterial aneurysmal dilatation. The right iliac artery is dissected and ligated proximally and distally (left panel). A microcatheter is inserted and advanced into the aorta and the balloon is inflated and then pulled back along the vessel (middle panel). Balloon passage is repeated twice and then the catheter is withdrawn and the iliac artery ligated (right panel).

Figure 15.3
Figure 15.3

Picture of balloon angioplasty in mouse. Lower left inserted picture shows abdominal incision and surgical exposure of the aorta for angioplasty balloon insertion and injury. Mag 10×. formula image, represents the right iliac artery into which the balloon is inserted; formula image, represents the abdominal aorta; formula image, represents the balloon inserted into the right iliac artery and advanced into the abdominal aorta where it is inflated with saline and dragged back and forth in the aorta to stretch the aorta and to induce damage.

Figure 15.4
Figure 15.4

Cross-sections of Hematoxylin and eosin (H & E) stained aorta isolated from mice 4 weeks after balloon angioplasty injury. Large areas of intimal plaque growth (arrows, A. Mag 200×) and aneurysmal dilatation (B. Mag 100×) were detected in ApoE-/- mice, but not in CCR2-/- (C. Mag 200×), PAI-1-/- (D. Mag 200×), Parp1-/- (E. Mag 200×), nor WT C57Bl/6 (F. Mag 200×) mice. A lower magnification picture is used in panel B to illustrate the marked increase in internal elastic lamina (IEL) diameter as marked by a double sided arrow demonstrating aneurysmal dilatation.

Figure 15.5
Figure 15.5

(A) Bar graphs illustrate differing plaque size with each mouse model. ApoE-/-mice with balloon injury have significantly larger plaque area (P < 0.004) than the other KO (knock out) mouse models or WT mice. (B) Bar graphs demonstrate increased mean internal elastic lamina (IEL) diameter in ApoE-/- mice when compared to WT and KO mouse models after angioplasty injury, evaluated at 4 weeks postangioplasty.

Figure 15.6
Figure 15.6

Fluorescence flow cytometric assay of mouse spleen cell isolates with dot plot displaying CD3-PerCP-Cy5.5 on the x-axis and CD4-PE-Cy7 on the y-axis.

Figure 15.7
Figure 15.7

Dramatic differences between the number of genes regulated by all treatments in THP-1 monocytes at 30 min and Jurkat T cells, then again with the total number of genes regulated at 4.5 h. A set of apparently shared target genes is detectable in THP-1 cells at 30 min after treatment with each of the viral proteins.

Figure 15.8
Figure 15.8

Serum D Dimer levels in blood samples from ACS patients treated with Serp-1 at 5 or 15 μg/kg or placebo after either Bare Metal Stent (BMS, A) or Drug Eluting Stent (DES, B) coronary implants after treatment with 5 or 15 mg of Serp-1 or Placebo.

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References

    1. Arnold K, Bordoli L, Kopp J, Schwede T. The SWISS-MODEL Workspace: A web-based environment for protein structure homology modelling. Bioinformatics. 2006;22:195–201. - PubMed
    1. Berry LR, Thong B, Chan AK. Comparison of recombinant and plasma-derived antithrombin biodistribution in a rabbit model. Thromb. Haemost. 2009;102:302–308. - PubMed
    1. Bouchecareilh M, Conkright JJ, Balch WE. Proteostasis strategies for restoring {alpha}1-antitrypsin deficiency. Proc. Am. Thorac. Soc. 2010;7:415–422. - PMC - PubMed
    1. Cameron* C, Hota-Mitchell* S, Chen L, Barrett J, Cao JX, Macaulay C, Willer D, Evans D, McFadden G. The complete DNA sequence of myxoma virus. Virology. 1999;264:298–318. (*denotes co-authorship) - PubMed
    1. Dai E, Guan H, Liu L, Little S, McFadden G, Vaziri S, Cao H, Ivanova IA, Bocksch L, Lucas AR. Serp-1, a viral anti-inflammatory serpin,regulates cellular serine proteinase and serpin responses to vascular injury. J. Biol. Chem. 2003;278:18563–18572. - PubMed

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