The Serpin Saga; Development of a New Class of Virus Derived Anti-Inflammatory Protein Immunotherapeutics

  • Alexandra Lucas
  • Liying Liu
  • Erbin Dai
  • Ilze Bot
  • Kasinath Viswanathan
  • Ganesh Munuswamy-Ramunujam
  • Jennifer A. Davids
  • Mee Y. Bartee
  • Jakob Richardson
  • Alexander Christov
  • Hao Wang
  • Colin Macaulay
  • Mark Poznansky
  • Robert Zhong
  • Leslie Miller
  • Erik Biessen
  • Mary Richardson
  • Collin Sullivan
  • Richard Moyer
  • Mark Hatton
  • David A. Lomas
  • Grant McFadden

Abstract

Serine proteinase inhibitors, also called serpins, are an ancient grouping of proteins found in primitive organisms from bacteria, protozoa and horseshoe crabs and thus likely present at the time of the dinosaurs, up to all mammals living today. The innate or inflammatory immune system is also an ancient metazoan regulatory system, providing the first line of defense against infection or injury. The innate inflammatory defense response evolved long before acquired, antibody dependent immunity. Viruses have developed highly effective stratagems that undermine and block a wide variety of host inflammatory and immune responses. Some of the most potent of these immune modifying strategies utilize serpins that have also been developed over millions of years, including the hijacking by some viruses for defense against host immune attacks. Serpins represent up to 2–10 percent of circulating plasma proteins, regulating actions as wide ranging as thrombosis, inflammation, blood pressure control and even hormone transport. Targeting serpin-regulated immune or inflammatory pathways makes evolutionary sense for viral defense and many of these virus-derived inhibitory proteins have proven to be highly effective, working at very low concentrations—even down to the femptomolar to picomolar range. We are studying these viral anti-inflammatory proteins as a new class of immunomodulatory therapeutic agents derived from their native viral source. One such viral serpin, Serp-1 is now in clinical trial (conducted by VIRON Therapeutics, Inc.) for acute unstable coronary syndromes (unstable angina and small heart attacks), representing a ’first in class’ therapeutic study. Several other viral serpins are also currendy under investigation as anti-inflammatory or anti-immune therapeutics. This chapter describes these original studies and the ongoing analysis of viral serpins as a new class of virus-derived immunotherapeutic.

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Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  • Alexandra Lucas
    • 1
    • 2
    • 3
  • Liying Liu
    • 1
    • 3
  • Erbin Dai
    • 1
    • 3
  • Ilze Bot
    • 4
  • Kasinath Viswanathan
    • 5
  • Ganesh Munuswamy-Ramunujam
    • 1
    • 2
  • Jennifer A. Davids
    • 1
    • 2
  • Mee Y. Bartee
    • 1
    • 2
  • Jakob Richardson
    • 6
  • Alexander Christov
    • 6
  • Hao Wang
    • 7
  • Colin Macaulay
    • 8
  • Mark Poznansky
    • 3
  • Robert Zhong
    • 4
  • Leslie Miller
    • 4
  • Erik Biessen
    • 4
  • Mary Richardson
    • 2
  • Collin Sullivan
    • 2
  • Richard Moyer
    • 2
  • Mark Hatton
    • 9
  • David A. Lomas
    • 10
  • Grant McFadden
    • 1
    • 2
  1. 1.Department of MedicineUniversity of FloridaGainesvilleUSA
  2. 2.Department of Molecular Genetics and MicrobiologyUniversity of FloridaGainesvilleUSA
  3. 3.Robarts Research InstituteUniversity of Western OntarioLondonCanada
  4. 4.University of MaastrichtMaastrichtThe Netherland
  5. 5.Oregon Health Sciences UniversityPortlandUSA
  6. 6.University of OklahomaOklahoma CityUSA
  7. 7.Oregon Health Sciences UniversityPortlandUSA
  8. 8.Viron Therapeutics, IncLondonCanada
  9. 9.McMaster UniversityHamiltonCanada
  10. 10.Cambridge Institute for Medical ResearchUniversity of CambridgeCambridgeUK
  11. 11.University of FloridaGainesvilleUSA

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