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Cited by 48Blood Coagulation and Thrombosis MechanismsProtease and Inhibitor MechanismsCoagulation, Bradykinin, Polyphosphates, and Angioedema

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Reactive Center Loop (RCL) Peptides Derived from Serpins Display Independent Coagulation and Immune Modulating Activities

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Ambadapadi, Sriram, Munuswamy-Ramanujam, Ganesh, Zheng, Donghang, Sullivan, Colin, Dai, Erbin, Morshed, Sufi, McFadden, Baron, Feldman, Emily, Pinard, Melissa, McKenna, Robert, Tibbetts, Scott, Lucas, Alexandra·2016·Journal of Biological Chemistry
DOI 10.1074/jbc.m115.704841PMC PMC4742751
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Abstract

Serpins regulate coagulation and inflammation, binding serine proteases in suicide-inhibitory complexes. Target proteases cleave the serpin reactive center loop scissile P1-P1' bond, resulting in serpin-protease suicide-inhibitory complexes. This inhibition requires a near full-length serpin sequence. Myxomavirus Serp-1 inhibits thrombolytic and thrombotic proteases, whereas mammalian neuroserpin (NSP) inhibits only thrombolytic proteases. Both serpins markedly reduce arterial inflammation and plaque in rodent models after single dose infusion. In contrast, Serp-1 but not NSP improves survival in a lethal murine gammaherpesvirus68 (MHV68) infection in interferon γ-receptor-deficient mice (IFNγR(-/-)). Serp-1 has also been successfully tested in a Phase 2a clinical trial. We postulated that proteolytic cleavage of the reactive center loop produces active peptide derivatives with expanded function. Eight peptides encompassing predicted protease cleavage sites for Serp-1 and NSP were synthesized and tested for inhibitory function in vitro and in vivo. In engrafted aorta, selected peptides containing Arg or Arg-Asn, not Arg-Met, with a 0 or +1 charge, significantly reduced plaque. Conversely, S-6 a hydrophobic peptide of NSP, lacking Arg or Arg-Asn with -4 charge, induced early thrombosis and mortality. S-1 and S-6 also significantly reduced CD11b(+) monocyte counts in mouse splenocytes. S-1 peptide had increased efficacy in plasminogen activator inhibitor-1 serpin-deficient transplants. Plaque reduction correlated with mononuclear cell activation. In a separate study, Serp-1 peptide S-7 improved survival in the MHV68 vasculitis model, whereas an inverse S-7 peptide was inactive. Reactive center peptides derived from Serp-1 and NSP with suitable charge and hydrophobicity have the potential to extend immunomodulatory functions of serpins.

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  • Administration of Serp1 causes a non-neutralizing antibody response, and the functional activity of the protein has been extended through development of small peptide mimetics that replicate the function of the full protein.

    “administration of Serp1 causes a non-neutralizing antibody response and subsequently the functional activity of the protein has been extended (and potential immunogenicity decreased) through development of small peptide mimetics that replicate the function of the full protein (Ambadapadi et al., 2016).”

    From Modulation of Host Immunity by Helminths: The Expanding Repertoire of Parasite Effector Molecules (2018) · cites this paper as Ambadapadi et al., 2016

  • Serp1 is an anti-inflammatory inhibitor of serine proteases.

    “Likewise, the myxoma viral protein Serp1 is an anti-inflammatory inhibitor of serine proteases;”

    From Modulation of Host Immunity by Helminths: The Expanding Repertoire of Parasite Effector Molecules (2018) · cites this paper as Ambadapadi et al., 2016

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Metadata

Authors
Ambadapadi, S., Munuswamy-Ramanujam, G., Zheng, D., Sullivan, C., Dai, E., Morshed, S., McFadden, B., Feldman, E., Pinard, M., McKenna, R., Tibbetts, S., & Lucas, A.
Affiliations
  • University of Florida (US)
  • University of Florida Health (US)
Corresponding author
Lucas, Alexandra
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2016-02
Volume
291
Issue
6
Pages
2874-2887
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m115.704841
PMC
PMC4742751
OpenAlex
W2182303898
Cited by
48
References
0
Citations by year
2026: 1 · 2025: 3 · 2023: 2 · 2022: 5 · 2021: 7 · 2020: 9 · 2019: 8 · 2018: 8 · 2017: 2 · 2016: 3
FWCI
3.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association (0855421 E)
  • National Institutes of Health (1RC1HL100202–01, AI100987–01A1)
Topics
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Health Sciences › Medicine › Hematology › Coagulation, Bradykinin, Polyphosphates, and Angioedema
Keywords
serpins, neuroserpin, thrombosis, atherosclerotic plaque, arterial inflammation, plasminogen activator inhibitor-1, murine gammaherpesvirus 68, vasculitis, monocyte activation, CD11b+ monocytes, immunomodulation, proteolytic cleavage sites
MeSH terms
Animals, Blood Coagulation, Disease Models, Animal, Herpesviridae Infections, Humans, Immunologic Factors, Membrane Proteins, Peptides, Vasculitis, Rhadinovirus, Mice, Knockout, Jurkat Cells, Mice

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