title: The serpin saga; development of a new class of virus derived anti-inflammatory protein immunotherapeutics.
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 currently 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.
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL 32610-0277, USA. alexandra.lucas@medicine.ufl.edu
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lucas
authors.forename: Liying
authors.initials: L
authors.lastname: Liu
authors.forename: Erbin
authors.initials: E
authors.lastname: Dai
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.forename: Kasinath
authors.initials: K
authors.lastname: Viswanathan
authors.forename: Ganesh
authors.initials: G
authors.lastname: Munuswamy-Ramunujam
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Davids
authors.forename: Mee Y
authors.initials: MY
authors.lastname: Bartee
authors.forename: Jakob
authors.initials: J
authors.lastname: Richardson
authors.forename: Alexander
authors.initials: A
authors.lastname: Christov
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Colin
authors.initials: C
authors.lastname: Macaulay
authors.forename: Mark
authors.initials: M
authors.lastname: Poznansky
authors.forename: Robert
authors.initials: R
authors.lastname: Zhong
authors.forename: Leslie
authors.initials: L
authors.lastname: Miller
authors.forename: Erik
authors.initials: E
authors.lastname: Biessen
authors.forename: Mary
authors.initials: M
authors.lastname: Richardson
authors.forename: Collin
authors.initials: C
authors.lastname: Sullivan
authors.forename: Richard
authors.initials: R
authors.lastname: Moyer
authors.forename: Mark
authors.initials: M
authors.lastname: Hatton
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D006801:Humans; D007154:Immune System Diseases / Q000628:therapy*; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D015843:Serpins / Q000627:therapeutic use*; D014764:Viral Proteins / Q000627:therapeutic use*; D014777:Virus Diseases / Q000628:therapy*
chemical_list: D000893:Anti-Inflammatory Agents; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D014764:Viral Proteins