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Biomolecules
Special Issues
Novel Applications and Mechanism of Proteinase Inhibitors
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Novel Applications and Mechanism of Proteinase Inhibitors

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Proteins".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 10105

Special Issue Editor

Dr. Sihong Song

E-Mail Website
Guest Editor
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA
Interests: functions and applications of alpha 1 antitrypsin (AAT) and SERPIN; development of novel treatment for autoimmune and inflammatory diseases; gene therapy using recombinant adeno-associated viral vectors (rAAV)

Special Issue Information

Dear Colleagues,

Balanced activities of proteinases and their inhibitors are critical in many biological processes to maintain a healthy condition. Overreactive proteinases are often involved in the pathogenesis of human diseases, including autoimmune, inflammatory and infectious diseases, as well as cancer. Therefore, targeting proteinase by synthetic or native proteinase inhibitors has therapeutic potential for the treatment of human diseases. In addition to the complexity of proteinase functions, the functions and applications of proteinase inhibitors remain elusive. Recent studies identified new proteinase inhibitors and revealed new mechanisms of proteinase inhibition. This Special Issue aims to publish recent findings that advance the therapeutic applications and the functional mechanism(s) of proteinase inhibitors.

Dr. Sihong Song
Guest Editor

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Keywords

  • proteinase inhibitor
  • serine proteinase inhibitor (SERPIN)
  • tissue damage
  • autoimmune disease
  • inflammatory disease
  • cancer
  • computationally designed drugs
  • drug screening

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Published Papers (4 papers)

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Research

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20 pages, 1753 KiB  
Article
Human Alpha-1 Antitrypsin Attenuates ENaC and MARCKS and Lowers Blood Pressure in Hypertensive Diabetic db/db Mice
by Carlos I. Lugo, Lauren P. Liu, Niharika Bala, Angelica G. Morales, Mohammed F. Gholam, Julia C. Abchee, Nasseem Elmoujahid, Ahmed Samir Elshikha, Rigena Avdiaj, Louis A. Searcy, Nancy D. Denslow, Sihong Song and Abdel A. Alli
Biomolecules 2023, 13(1), 66; https://doi.org/10.3390/biom13010066 - 29 Dec 2022
Cited by 7 | Viewed by 2506
Abstract
Hypertension may develop before or after the onset of diabetes and it is known to increase the risk of developing diabetic nephropathy. Alpha-1 antitrypsin (AAT) is a multi-functional protein with beneficial effects in various diseases but its role in reducing blood pressure in [...] Read more.
Hypertension may develop before or after the onset of diabetes and it is known to increase the risk of developing diabetic nephropathy. Alpha-1 antitrypsin (AAT) is a multi-functional protein with beneficial effects in various diseases but its role in reducing blood pressure in the diabetic kidney has not been thoroughly studied. Like blood pressure, epithelial sodium channels (ENaC) and its adaptor protein myristoylated alanine-rich C-kinase substrate (MARCKS) are regulated by circadian rhythms. Our hypothesis is that administration of human AAT (hAAT) reduces blood pressure in hypertensive diabetic mice by attenuating membrane expression of ENaC and its association with the actin cytoskeleton. First, we show hAAT administration results in reduced blood pressure in diabetic db/db mice compared to vehicle treatment in both the inactive and active cycles. Western blotting and immunohistochemistry analyses showed a reduction of ENaC and the actin cytoskeleton protein, MARCKS in the kidneys of diabetic db/db mice treated with hAAT compared to vehicle. hAAT treatment resulted in elevated amounts of extracellular vesicles present in the urine of diabetic db/db mice compared to vehicle treatment both in the inactive and active cycles. Multiple hexosylceramides, among other lipid classes increased in urinary EVs released from hAAT treated hypertensive diabetic mice compared to vehicle treated mice. Taken together, these data suggest hAAT treatment could normalize blood pressure in the diabetic kidney in a mechanism involving attenuation of renal ENaC and MARCKS protein expression and possibly ceramide metabolism to hexosylceramide in kidney cells. Full article
(This article belongs to the Special Issue Novel Applications and Mechanism of Proteinase Inhibitors)
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12 pages, 4288 KiB  
Article
Secretory Leucoprotease Inhibitor (SLPI) Promotes Survival during Acute Pseudomonas aeruginosa Infection by Suppression of Inflammation Rather Than Microbial Killing
by Megan Osbourn, Aoife M. Rodgers, Alice V. Dubois, Donna M. Small, Fiachra Humphries, Nezira Delagic, Paul N. Moynagh, Sinéad Weldon, Clifford C. Taggart and Rebecca J. Ingram
Biomolecules 2022, 12(12), 1728; https://doi.org/10.3390/biom12121728 - 22 Nov 2022
Cited by 7 | Viewed by 2552
Abstract
Secretory leucoprotease inhibitor (SLPI) has multifaceted functions, including inhibition of protease activity, antimicrobial functions, and anti-inflammatory properties. In this study, we show that SLPI plays a role in controlling pulmonary Pseudomonas aeruginosa infection. Mice lacking SLPI were highly susceptible to P. aeruginosa infection, [...] Read more.
Secretory leucoprotease inhibitor (SLPI) has multifaceted functions, including inhibition of protease activity, antimicrobial functions, and anti-inflammatory properties. In this study, we show that SLPI plays a role in controlling pulmonary Pseudomonas aeruginosa infection. Mice lacking SLPI were highly susceptible to P. aeruginosa infection, however there was no difference in bacterial burden. Utilising a model of P. aeruginosa LPS-induced lung inflammation, human recombinant SLPI (hrSLPI) administered intraperitoneally suppressed the recruitment of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and resulted in reduced BALF and serum levels of inflammatory cytokines and chemokines. This anti-inflammatory effect of hrSLPI was similarly demonstrated in a systemic inflammation model induced by intraperitoneal injection of LPS from various bacteria or lipoteichoic acid, highlighting the broad anti-inflammatory properties of hrSLPI. Moreover, in bone-marrow-derived macrophages, hrSLPI reduced LPS-induced phosphorylation of p-IkB-α, p-IKK-α/β, p-P38, demonstrating that the anti-inflammatory effect of hrSLPI was due to the inhibition of the NFκB and MAPK pathways. In conclusion, administration of hrSLPI attenuates excessive inflammatory responses and is therefore, a promising strategy to target inflammatory diseases such as acute respiratory distress syndrome or sepsis and could potentially be used to augment antibiotic treatment. Full article
(This article belongs to the Special Issue Novel Applications and Mechanism of Proteinase Inhibitors)
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16 pages, 3420 KiB  
Article
Human Alpha 1 Antitrypsin Suppresses NF-κB Activity and Extends Lifespan in Adult Drosophila
by Ye Yuan, Max Van Belkum, Alana O’Brien, Alain Garcia, Karla Troncoso, Ahmed S. Elshikha, Lei Zhou and Sihong Song
Biomolecules 2022, 12(10), 1347; https://doi.org/10.3390/biom12101347 - 22 Sep 2022
Cited by 1 | Viewed by 2290
Abstract
Human alpha 1 antitrypsin (hAAT) is a multifunctional protein that has been shown to have anti-inflammatory and cellular protective properties. While previous studies demonstrated the antiaging potential of hAAT, the mechanism(s) underlying the antiaging effect remain elusive. In this study, we performed a [...] Read more.
Human alpha 1 antitrypsin (hAAT) is a multifunctional protein that has been shown to have anti-inflammatory and cellular protective properties. While previous studies demonstrated the antiaging potential of hAAT, the mechanism(s) underlying the antiaging effect remain elusive. In this study, we performed a detailed analysis of transcriptomic data that indicated that NF-κB-targeted genes and NF-κB-regulated pathways were selectively inhibited by hAAT treatment. We further showed that the first detectable impact of hAAT treatment was the inhibition of the nuclear activity of NF-κB. Subsequently, hAAT treatment suppressed the mRNA levels of NF-κB-targeted genes, as well as NF-κB itself (P65 and P50), in human senescent cells. Using Drosophila models, we further examined the impact of hAAT on locomotor activity and endurance. Finally, using an adult-specific promotor, we demonstrated that overexpression of hAAT in the late stage of life significantly extended the lifespan of transgenic flies. These results extend the current understanding of the anti-inflammatory function of hAAT. Full article
(This article belongs to the Special Issue Novel Applications and Mechanism of Proteinase Inhibitors)
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Review

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23 pages, 1357 KiB  
Review
Viral SERPINS—A Family of Highly Potent Immune-Modulating Therapeutic Proteins
by Kyle Varkoly, Roxana Beladi, Mostafa Hamada, Grant McFadden, James Irving and Alexandra R. Lucas
Biomolecules 2023, 13(9), 1393; https://doi.org/10.3390/biom13091393 - 15 Sep 2023
Cited by 5 | Viewed by 2157
Abstract
Serine protease inhibitors, SERPINS, are a highly conserved family of proteins that regulate serine proteases in the central coagulation and immune pathways, representing 2–10% of circulating proteins in the blood. Serine proteases form cascades of sequentially activated enzymes that direct thrombosis (clot formation) [...] Read more.
Serine protease inhibitors, SERPINS, are a highly conserved family of proteins that regulate serine proteases in the central coagulation and immune pathways, representing 2–10% of circulating proteins in the blood. Serine proteases form cascades of sequentially activated enzymes that direct thrombosis (clot formation) and thrombolysis (clot dissolution), complement activation in immune responses and also programmed cell death (apoptosis). Virus-derived serpins have co-evolved with mammalian proteases and serpins, developing into highly effective inhibitors of mammalian proteolytic pathways. Through interacting with extracellular and intracellular serine and cysteine proteases, viral serpins provide a new class of highly active virus-derived coagulation-, immune-, and apoptosis-modulating drug candidates. Viral serpins have unique characteristics: (1) function at micrograms per kilogram doses; (2) selectivity in targeting sites of protease activation; (3) minimal side effects at active concentrations; and (4) the demonstrated capacity to be modified, or fine-tuned, for altered protease targeting. To date, the virus-derived serpin class of biologics has proven effective in a wide range of animal models and in one clinical trial in patients with unstable coronary disease. Here, we outline the known viral serpins and review prior studies with viral serpins, considering their potential for application as new sources for immune-, coagulation-, and apoptosis-modulating therapeutics. Full article
(This article belongs to the Special Issue Novel Applications and Mechanism of Proteinase Inhibitors)
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