Viral Serpin Therapeutics

Chen, Hao; Zheng, Duo; Davids, Jennifer; Bartee, Mee Yong; Dai, Erbin; Liu, Liying; Petrov, L. Yu.; Macaulay, Colin; Thoburn, Robert; Sobel, Eric S.; Moyer, Richard W.; McFadden, Grant; Lucas, Alexandra

doi:10.1016/b978-0-12-386471-0.00015-8

Cited by 19 publications

(7 citation statements)

References 55 publications

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“…A series of donor renal allografts from either C57Bl/6 wild type (WT) or Ndst1 −/− were transplanted into BALB/c mice. Mice with WT or Ndst1 −/− donor allografts were treated with either saline control, M-T7 or individual mutated constructs (M-T7-His 6X , F 137 D, R 171 E, or E 209 I; 6–10 mice per donor organ strain and per treatment) (Table 1 ) 29 , 34 , 52 . Donor renal allografts were transplanted into BALB/c mice after resection of both kidneys under general anesthetic.…”

Section: Methodsmentioning

confidence: 99%

Selective Deletion of Heparan Sulfotransferase Enzyme, Ndst1, in Donor Endothelial and Myeloid Precursor Cells Significantly Decreases Acute Allograft Rejection

Chen

Ambadapadi

Wakefield

et al. 2018

Sci Rep

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Early damage to transplanted organs initiates excess inflammation that can cause ongoing injury, a leading cause for late graft loss. The endothelial glycocalyx modulates immune reactions and chemokine-mediated haptotaxis, potentially driving graft loss. In prior work, conditional deficiency of the glycocalyx-modifying enzyme N-deacetylase-N-sulfotransferase-1 (Ndst1f/f TekCre+) reduced aortic allograft inflammation. Here we investigated modification of heparan sulfate (HS) and chemokine interactions in whole-organ renal allografts. Conditional donor allograft Ndst1 deficiency (Ndst1−/−; C57Bl/6 background) was compared to systemic treatment with M-T7, a broad-spectrum chemokine-glycosaminoglycan (GAG) inhibitor. Early rejection was significantly reduced in Ndst1−/− kidneys engrafted into wildtype BALB/c mice (Ndst1+/+) and comparable to M-T7 treatment in C57Bl/6 allografts (P < 0.0081). M-T7 lost activity in Ndst1−/− allografts, while M-T7 point mutants with modified GAG-chemokine binding displayed a range of anti-rejection activity. CD3+ T cells (P < 0.0001), HS (P < 0.005) and CXC chemokine staining (P < 0.012), gene expression in NFκB and JAK/STAT pathways, and HS and CS disaccharide content were significantly altered with reduced rejection. Transplant of donor allografts with conditional Ndst1 deficiency exhibit significantly reduced acute rejection, comparable to systemic chemokine-GAG inhibition. Modified disaccharides in engrafted organs correlate with reduced rejection. Altered disaccharides in engrafted organs provide markers for rejection with potential to guide new therapeutic approaches in allograft rejection.

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Section: Methodsmentioning

confidence: 99%

Selective Deletion of Heparan Sulfotransferase Enzyme, Ndst1, in Donor Endothelial and Myeloid Precursor Cells Significantly Decreases Acute Allograft Rejection

Chen

Ambadapadi

Wakefield

et al. 2018

Sci Rep

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“…In addition to small molecules, protein-based serine protease inhibitors have also been reported to be effective against viral infections. Serpins, including serp-1 and serp-2 are derived from myxomavirus and exhibit immunomodulatory effects [ 105 ]. Serp-1 also improved the survival of mice infected with an unrelated virus-like mouse-adapted Zaire ebolavirus and murine γ-herpes virus 68 [ 106 ].…”

Section: Clinical Approachesmentioning

confidence: 99%

Emerging Therapeutic Modalities against COVID-19

et al. 2020

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The novel SARS-CoV-2 virus has quickly spread worldwide, bringing the whole world as well as the economy to a standstill. As the world is struggling to minimize the transmission of this devastating disease, several strategies are being actively deployed to develop therapeutic interventions. Pharmaceutical companies and academic researchers are relentlessly working to investigate experimental, repurposed or FDA-approved drugs on a compassionate basis and novel biologics for SARS-CoV-2 prophylaxis and treatment. Presently, a tremendous surge of COVID-19 clinical trials are advancing through different stages. Among currently registered clinical efforts, ~86% are centered on testing small molecules or antibodies either alone or in combination with immunomodulators. The rest ~14% of clinical efforts are aimed at evaluating vaccines and convalescent plasma-based therapies to mitigate the disease's symptoms. This review provides a comprehensive overview of current therapeutic modalities being evaluated against SARS-CoV-2 virus in clinical trials.

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“…Purification schemes for Serp-1 were based on similar protocols that have been used to produce good manufacturing product (GMP) quality serpin protein for use in patients developed by Viron Therapeutics. Serp-1 protein is estimated to be ∼95% pure using Commassie-stained sodium dodecyl sulfate (SDS)–polyacrylamide gels and reverse-phase high-performance liquid chromatography. ,, …”

Section: Methodsmentioning

confidence: 99%

“…When the Serp-1 gene is deleted, either naturally, as in the Shope fibroma virus, or experimentally in wild-type Myxomavirus , the virus turns from a lethal pathogen to a benign, easily eliminated infection . In mammals, Serp-1 is an effective anti-inflammatory and coagulation pathway modulating serine protease inhibitor, a serpin, that inhibits clot forming and clot dissolving, thrombosis and thrombolysis pathways, respectively. , The Serp-1 immunomodulatory function has a demonstrated capacity to significantly reduce inflammatory vasculitis and improve survival in a lethal mouse Herpesviral (MHV68) sepsis model, reducing recurrent atherosclerotic plaque growth after balloon angioplasty, stent implant (restenosis), arthritis, and preventing transplant vascular disease and rejection . In a Phase IIa clinical trial, Serp-1 successfully reduced markers of myocardial damage in patients with unstable coronary syndromes (unstable angina and small heart attacks), representing a new class of virus-derived protein therapeutics. , Recently, Serp-1 has been demonstrated to improve survival in a mouse lupus lung hemorrhage model (W. Reeves, personal communication).…”

mentioning

confidence: 99%

Crystal Structure of Cleaved Serp-1, a Myxomavirus-Derived Immune Modulating Serpin: Structural Design of Serpin Reactive Center Loop Peptides with Improved Therapeutic Function

Mahon

Ambadapadi

Yaron³

et al. 2018

Biochemistry

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The Myxomavirus-derived protein Serp-1 has potent anti-inflammatory activity in models of vasculitis, lupus, viral sepsis, and transplant. Serp-1 has also been tested successfully in a Phase IIa clinical trial in unstable angina, representing a "first-in-class" therapeutic. Recently, peptides derived from the reactive center loop (RCL) have been developed as stand-alone therapeutics for reducing vasculitis and improving survival in MHV68-infected mice. However, both Serp-1 and the RCL peptides lose activity in MHV68-infected mice after antibiotic suppression of intestinal microbiota. Here, we utilize a structure-guided approach to design and test a series of next-generation RCL peptides with improved therapeutic potential that is not reduced when the peptides are combined with antibiotic treatments. The crystal structure of cleaved Serp-1 was determined to 2.5 Å resolution and reveals a classical serpin structure with potential for serpin-derived RCL peptides to bind and inhibit mammalian serpins, plasminogen activator inhibitor 1 (PAI-1), anti-thrombin III (ATIII), and α-1 antitrypsin (A1AT), and target proteases. Using in silico modeling of the Serp-1 RCL peptide, S-7, we designed several modified RCL peptides that were predicted to have stronger interactions with human serpins because of the larger number of stabilizing hydrogen bonds. Two of these peptides (MPS7-8 and -9) displayed extended activity, improving survival where activity was previously lost in antibiotic-treated MHV68-infected mice (P < 0.0001). Mass spectrometry and kinetic assays suggest interaction of the peptides with ATIII, A1AT, and target proteases in mouse and human plasma. In summary, we present the next step toward the development of a promising new class of anti-inflammatory serpin-based therapeutics.

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Viral Serpin Therapeutics

Cited by 19 publications

References 55 publications

Selective Deletion of Heparan Sulfotransferase Enzyme, Ndst1, in Donor Endothelial and Myeloid Precursor Cells Significantly Decreases Acute Allograft Rejection

Selective Deletion of Heparan Sulfotransferase Enzyme, Ndst1, in Donor Endothelial and Myeloid Precursor Cells Significantly Decreases Acute Allograft Rejection

Emerging Therapeutic Modalities against COVID-19

Crystal Structure of Cleaved Serp-1, a Myxomavirus-Derived Immune Modulating Serpin: Structural Design of Serpin Reactive Center Loop Peptides with Improved Therapeutic Function

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