Viral SERPINS—A Family of Highly Potent Immune-Modulating Therapeutic Proteins
Abstract
:1. Introduction
1.1. Serpins—Serine Protease Inhibitors
1.2. Serpin Regulation of Coagulation and Immune Responses
Viral Serpin | Inflammatory Disorder | Target/Outcomes | Subjects Studied | Reference |
---|---|---|---|---|
Serp-1 | Atherosclerotic Plaque Acute coronary syndromes with stent implant |
|
| [20,24] |
Angioplasty injury and intimal plaque restenosis | Efficacy and Mechanism extensively studied | Rabbits, Rats, Mice, Swine/Reduced intimal hyperplasia and inflammation in rodents and rabbits | [20,21,22] | |
Aortic Allograft Transplant | Established uPAR as central for Serp-1 therapeutic efficacy | Mouse and rat | [21,33,42] | |
MHV68—Mouse Herpes virus aortitis and lung inflammation | Serp-1 reduced mortality, whereas NSP did not Reduction in monocytes and pro-inflammatory cytokines, reduced lung hemorrhage, NSP not effective | Mice | [26,43] | |
Carotid compression—Atherosclerotic Plaque | Reduction in carotid arterial inflammation and plaque | Mice | [22] | |
Giant Cell Arteritis Human Temporal artery biopsy implants | Reduction in monocytes and pro-inflammatory cytokines | SCID Mice | [25] | |
Ebola infection | Reduced liver damage and improved survival | Mice | [26] | |
Diffuse Alveolar Hemorrhage (DAH) in Pristane induced Systemic Lupus Erythematosus | Reduced uPAR and Complement and reduced macrophage infiltrates | Mice | [17,44] | |
SARS-CoV-2 | Reduction in M1 macrophage recruitment in cardiac and pulmonary tissue | Mouse adapted SARS models in C57Bl/6 and BALB/c mice | [39] | |
Colitis model | Serp-1 reduced mortality | Mice | In preparation | |
Collagen induced arthritis | Reduced joint swelling without antibodies to Serp-1 treatment | Rats | [28] | |
Retinal Inflammation—Uveitis Corneal wound healing | Retinal-Intra-vitreal injection of AAV vector expressing Serp-1 Corneal—topical | Mice | [29,45] | |
Periodontal bacteria with associated increased atherosclerotic plaque | Decreased pro-inflammatory markers and reduced plaque | Mice | [30] | |
Scar Reduction in Wound Healing | Accelerated wound healing-Improved collagen formation in wound bed Effects blocked by uPAR antibody | Mice | [31] | |
Transplant Rejection | Rat and Mouse renal, aortic and heterotopic heart allografts Rat to mouse cardiac xenografts | Human, Rat, Mice | [32,33,46,47] | |
Angiogenesis | Effects blocked by uPAR antibody in wound healing Reduced availability of VEGF | Chicken angiogenesis CAM Model Mouse wound healing model | [31,34] | |
Pancreatic Cancer subcutaneous implants | Reduced tumor weight for pancreatic cell line implant and reduced macrophage infiltration | Human to Mice cell xenografts in SCID mice | [35] | |
Spinal Cord Injury Balloon angioplasty crush injury | Improved motor function, reduced inflammation and improved neuronal growth Local infusion | Rats Local infusion | [36,37] | |
Duchenne Muscular Dystrophy | Reduced leukocyte invasion, Improved myofibril organization Serp-1, PEGSerp-1 | Double knock out DMD Mice | [38] | |
Serp-2 | Angioplasty injury and intimal hyperplasia | Reduced inflammation and intimal hyperplasia | Mice | [23,40] |
Carotid cuff compression injury in hyperlipidemic mouse models | Reduction in aortic Atherosclerotic Plaque Development | ApoEnull Mice carotid cuff compression | [40] | |
Aortic Transplant | Reduced intimal plaque and inflammation Inhibition of Granzyme-B mediated apoptosis | Mouse aortic Allografts (1) WT C57Bl/6 to BALB/c and (2) Granzyme B KO donor allografts | [40] | |
Liver Transplant | Improved survival, reduced hepatocyte necrosis | Mice | [41] | |
SPI-1 | Chemotherapy | Multi-pathway inhibitor of apoptosis | In vitro | [48] |
Viral Host Defense and Vaccination | Mice, in vitro | [48] | ||
SPI-2 and CrmA | Chemotherapy | Multi-pathway inhibitor of apoptosis | In vitro | [39,40,48] |
Neurodegeneration | Mice, in vitro | [49] | ||
Fulminant Liver Failure | Mice, in vitro | [50,51] | ||
Autoimmune Hepatitis | Reduction in inflammatory cell (CD11), inhibitor of apoptosis | Mice, in vitro | [50,51] | |
Ischemic-Reperfusion Injury/Chemotherapeutic Cardiotoxicity | Multi-pathway inhibitor of apoptosis | Mice, in vitro | [52,53] | |
SPI-3 | Hemophilia | Inhibits uPA, plasmin, and tPA | Mice, in vitro–proposed function | [54,55] |
2. Virus-Derived Serpins
2.1. Poxvirus Serpins
- 2-1A).
- Serp-1
- 2.1A)-1.
- Acute and Chronic Inflammatory Diseases
- 2.1A)-1-1.
- Atherosclerotic Disease
- 2.1A)-1-1-1.
- Percutaneous Coronary Intervention (PCI) and Restenosis in Unstable Atherosclerotic Plaque—preclinical testing
- 2.1A)-1-1-2.
- Periodontal Disease and Associated Atherosclerotic Plaque Development
- 2.1A)-1-1-3.
- Acute Coronary Syndrome (ACS)—Clinical Trial
- 2.1A)-1-2.
- Inflammatory Vasculitis Syndromes—Giant Cell Arteritis and Takayasu Disease
- 2.1A)-1-2-1.
- Giant Cell Arteritis
- 2.1A)-1-2-2.
- Mouse Gamma Herpes Viral Infection (MHV68)
- 2.1A)-1-3.
- Autoimmune Disorders
- 2.1A)-1-3-1.
- Transplant Rejection
- 2.1A)-1-3-2.
- Rheumatoid Arthritis
- 2.1A)-1-4.
- Systemic Lupus Erythematosus and Diffuse Alveolar Hemorrhage (DAH)
- 2.1A)-1-5.
- Neurological, Musculoskeletal and Ophthalmological Disorders
- 2.1A)-1-5-1.
- Spinal Cord Injury
- 2.1A)-1-5-2.
- Duchenne Muscular Dystrophy
- 2.1A)-1-5-3.
- Retinal Inflammation
- 2.1A)-1-6.
- Wound Healing
- 2.1A)-1-7.
- Cancer Therapeutics
- 2.1A)-1-8.
- Severe Acute Respiratory Distress syndromes, SARS-CoV-2 Infection
- 2-1B).
- Serp-2 and CrmA
- 2-1B)-1.
- Atherosclerotic Plaque and Restenosis following Angioplasty Injury
- 2-1B)-1-2.
- Transplant Rejection
- 2-1B)-1-2-1.
- Intimal Plaque Hyperplasia in Aortic Transplant
- 2-1B)-1-2-2.
- Ischemia-Reperfusion Injury in Liver Transplant
- 2-1C).
- Orthopoxviral Serpins Spi1, Spi2 and Spi3
- 2-1C)-1.
- Spi1 and Spi2
- 2.1C)-2.
- Spi2/CrmA
- 2.1C)-2-3.
- Spi3
- 2.1C)-2-3-1.
- Inflammation and Vascular Permeability
- 2-2).
- Herpesviral serpins
- 2-3).
- Plant Viral Serpins
- 2-4).
- Arthropod Serpins and Athropod-Viral Serpins—Baculovirus Serpins
2.2. Nucleopolyhedroviral Serpins
2.3. Rice Stripe Virus Serpins (RSV)
3. Modifying Viral Serpins—New Therapeutic Constructs
4. Conclusions
Funding
Acknowledgments
Conflicts of Interest
References
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Varkoly, K.; Beladi, R.; Hamada, M.; McFadden, G.; Irving, J.; Lucas, A.R. Viral SERPINS—A Family of Highly Potent Immune-Modulating Therapeutic Proteins. Biomolecules 2023, 13, 1393. https://doi.org/10.3390/biom13091393
Varkoly K, Beladi R, Hamada M, McFadden G, Irving J, Lucas AR. Viral SERPINS—A Family of Highly Potent Immune-Modulating Therapeutic Proteins. Biomolecules. 2023; 13(9):1393. https://doi.org/10.3390/biom13091393
Chicago/Turabian StyleVarkoly, Kyle, Roxana Beladi, Mostafa Hamada, Grant McFadden, James Irving, and Alexandra R. Lucas. 2023. "Viral SERPINS—A Family of Highly Potent Immune-Modulating Therapeutic Proteins" Biomolecules 13, no. 9: 1393. https://doi.org/10.3390/biom13091393