Review
Medicine, General & Internal
Marcelo B. Zani, Aquiles M. Sant'Ana, Rafael C. Tognato, Jair R. Chagas, Luciano Puzer
Summary: Human tissue Kallikrein-related peptidases (hKLKs) play important roles in skin desquamation and skin diseases by cleaving corneodesmosomes and activating the PAR2 pathway. Inhibition of hKLKs shows promise as a therapeutic approach for improving the quality of life in patients with skin diseases.
FRONTIERS IN MEDICINE
(2022)
Article
Cell Biology
Joseph Chavarria-Smith, Cecilia P. C. Chiu, Janet K. Jackman, Jianping Yin, Juan Zhang, Jason A. Hackney, Wei-Yu Lin, Tulika Tyagi, Yonglian Sun, Janet Tao, Debra Dunlap, William D. Morton, Swapnil Ghodge, Henry R. Maun, Hong Li, Hilda Hernandez-Barry, Kelly M. Loyet, Emily Chen, John Liu, Christine Tam, Brian L. Yaspan, Hao Cai, Mercedesz Balazs, Joseph R. Arron, Jing Li, Arthur J. Wittwer, Rajita Pappu, Cary D. Austin, Wyne P. Lee, Robert A. Lazarus, Jawahar Sudhamsu, James T. Koerber, Tangsheng Yi
Summary: This article discusses the importance of the epidermis and the mechanisms related to skin diseases involving KLK and LEKTI. The study discovered antibodies that can inhibit KLK5 and KLK7, which can protect the skin by improving barrier integrity and reducing inflammation.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Tatiana F. R. Costa, Amy Goundry, Alexandre Morrot, Dennis J. Grab, Jeremy C. Mottram, Ana Paula C. A. Lima
Summary: This study reveals the mechanism of Trypanosoma brucei rhodesiense penetration through the blood-brain barrier and causing sleeping sickness. The Cathepsin L-like cysteine peptidase and its endogenous inhibitor ICP play important roles in the infection process and regulate inflammatory responses. The results suggest that ICP helps to downregulate inflammatory responses and control the infection.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Physical
Andreas H. Simon, Sandra Liebscher, Ariunkhur Kattner, Christof Kattner, Frank Bordusa
Summary: Trypsin is a widely used serine protease with high catalytic activity and stability. By altering its calcium-binding site, calcium-independent trypsin with enhanced thermal and functional stability can be obtained.
Article
Microbiology
Mrinalini Roy, Aadish Rawat, Sanket Kaushik, Anupam Jyoti, Vijay Kumar Srivastava
Summary: This article reviews the endogenous inhibitors of cysteine proteases in three major pathogenic parasitic protozoa. The inhibitors target proteases involved in host-parasite interactions and are also involved in other functions of the parasites. They show limited sequence homology and are linked to parasite biology and evolution.
MICROBIOLOGICAL RESEARCH
(2022)
Review
Pharmacology & Pharmacy
Brice Korkmaz, Anne-Sophie Lamort, Roxane Domain, Celine Beauvillain, Artur Gieldon, Ali Oender Yildirim, Georgios T. Stathopoulos, Moez Rhimi, Dieter E. Jenne, Ralph Kettritz
Summary: Cathepsin C plays a crucial role in cancer development and metastasis, and is considered as a potential therapeutic target for various types of cancer. Recent studies have highlighted the important interaction between tumor-associated CatC, NSPs, and NETs in cancer progression, providing new insights for cancer treatment strategies.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Immunology
Ofir Fursht, Mirit Liran, Yuval Nash, Vijay Krishna Medala, Dor Ini, Tabitha Grace Royal, Guy Goldsmith, Limor Nahary, Itai Benhar, Dan Frenkel
Summary: Inhibiting insulin-degrading enzyme (IDE) with an IDE-specific antibody shows promise in improving insulin activity in diabetes. Researchers have isolated an IDE-specific antibody that can specifically inhibit insulin degradation by IDE and demonstrated its efficacy in improving insulin activity in a diabetes mouse model.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Allergy
Paula Busse, Allen Kaplan
Summary: This article provides an overview of hereditary angioedema (HAE), a rare genetic disease characterized by nonpruritic angioedema. The study discusses the classification of HAE and the underlying genetic mutations that cause the condition. It also explores the mechanism of HAE and the development of plasma kallikrein inhibitors as a treatment option. The article highlights the importance of understanding and managing HAE to improve patient outcomes.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE
(2022)
Article
Biochemistry & Molecular Biology
Anne Kunath, Juliane Weiner, Kerstin Krause, Maren Rehders, Anastasija Pejkovska, Martin Gericke, Martin L. Biniossek, Sebastian Dommel, Matthias Kern, Aleix Ribas-Latre, Oliver Schilling, Klaudia Brix, Michael Stumvoll, Nora Kloeting, John T. Heiker, Matthias Bluher
Summary: Increased plasma and adipose tissue protease activity has been observed in patients with type 2 diabetes and obesity, with specific proteases potentially contributing to the link between obesity, adipose tissue inflammation, and metabolic diseases. Ablation of the serine protease Klk7 in adipose tissue has shown to preserve insulin sensitivity, protect against obesity-related inflammation, and regulate body weight and energy metabolism, indicating the potential application of specific KLK7 inhibitors in combatting obesity and associated inflammation.
Review
Biochemistry & Molecular Biology
Alba Ramos-Llorca, Camilla Scarpellini, Koen Augustyns
Summary: This review examines the implications of proteases in the development and severity of dry eye disease and discusses the progress in utilizing protease inhibitors as potential therapeutic tools.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Immunology
Chendi Jing, Chenghua Liu, Yu Liu, Ruli Feng, Run Cao, Zhangchun Guan, Bo Xuan, Yaping Gao, Qi Wang, Nana Yang, Yuanfang Ma, Lefu Lan, Jiannan Feng, Beifen Shen, Hui Wang, Yanyan Yu, Guang Yang
Summary: The alkaline protease (AprA) secreted by Pseudomonas aeruginosa may aggravate infection by destroying formed NETs, an effect further enhanced by its antibodies. AprA degrades NET components, but does not affect NET formation.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Food Science & Technology
Andrea Nieto-Veloza, Zhihong Wang, Qixin Zhong, Doris D'Souza, Hari B. Krishnan, Vermont P. Dia
Summary: This study assessed the in vivo anti-inflammatory properties of Lunasin protease inhibitor concentrate (LPIC). In vitro tests showed that LPIC induced the production of nitric oxide and maintained cytokine levels. In vivo experiments demonstrated that LPIC significantly attenuated tissue damage in ulcerative colitis.
FOOD SCIENCE AND HUMAN WELLNESS
(2022)
Article
Biochemical Research Methods
Zhenyu Ma, Kaijie Mu, Jingyi Zhu, Min Xiao, Lushan Wang, Xukai Jiang
Summary: Thermophilic enzymes are highly desired in industrial applications due to their efficient catalytic activity at high temperature. However, most enzymes exhibit inferior thermostability and it remains challenging to identify the optimal sites for designing mutations to improve protein stability. In this study, we used topological analysis and molecular dynamics simulations to efficiently pinpoint the thermally-unstable regions in protein structures. By analyzing the intramolecular hydrogen bonding interactions and weak spots, we were able to design virtual mutations that increased the protein structural stability.
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
(2023)
Article
Chemistry, Analytical
Daniella Romano de Carvalho, Valdecir Farias Ximenes, Milton Groppo, Carmen Lucia Cardoso
Summary: In this study, porcine pancreas KLK was covalently immobilized on an NHS-activated Sepharose matrix to obtain KLK-Sepharose-NHS, showing high recovered activity and maintained recognition ability of synthetic substrates. Inhibition studies using leupeptin as a reference inhibitor revealed the effectiveness and potential of the developed bioassay in screening and identifying KLK ligands.
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
(2021)
Review
Dermatology
Shin Morizane, Ko Sunagawa, Hayato Nomura, Mamoru Ouchida
Summary: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by epidermal barrier dysfunction, allergic inflammation, and itching. Excessive protease activities, especially serine proteases, play a crucial role in AD pathogenesis by disrupting the epidermal barrier and facilitating allergen and microorganism invasion. Further understanding of the regulation of serine protease activities may lead to the development of new therapeutic strategies for AD.
JOURNAL OF DERMATOLOGICAL SCIENCE
(2022)
Article
Immunology
Nicholas A. Turner, Bobby G. Warren, Maria F. Gergen-Teague, Rachel M. Addison, Bechtler Addison, William A. Rutala, David J. Weber, Daniel J. Sexton, Deverick J. Anderson
Summary: Fidaxomicin and vancomycin are more effective in reducing C. difficile shedding and environmental contamination compared to metronidazole. Treatment choice may play a role in reducing healthcare-associated C. difficile transmission.
CLINICAL INFECTIOUS DISEASES
(2022)
Article
Biochemistry & Molecular Biology
Pooja Kesari, Anuradha Deshmukh, Nikhil Pahelkar, Abhishek B. Suryawanshi, Ishan Rathore, Vandana Mishra, John H. Dupuis, Huogen Xiao, Alla Gustchina, Jan Abendroth, Mehdi Labaied, Rickey Y. Yada, Alexander Wlodawer, Thomas E. Edwards, Donald D. Lorimer, Prasenjit Bhaumik
Summary: Plasmodium falciparum plasmepsin X (PfPMX), an essential protein for the survival of the deadliest malaria parasite, has been identified as a potential drug target. The crystal structure of PfPMX zymogen, which contains a novel fold of its prosegment, has been determined for the first time. The study provides insights into the inactivation, maturation, and inhibition of PfPMX, which could aid in the development of potent inhibitors against similar proteases from apicomplexan parasites.
Article
Biochemical Research Methods
Imani Porter, Trinity Neal, Zion Walker, Dylan Hayes, Kayla Fowler, Nyah Billups, Anais Rhoades, Christian Smith, Kaelyn Smith, Bart L. Staker, David M. Dranow, Stephen J. Mayclin, Sandhya Subramanian, Thomas E. Edwards, Peter J. Myler, Oluwatoyin A. Asojo
Summary: Members of the bacterial genus Brucella, which can be used as biological warfare agents, cause brucellosis, a zoonotic disease affecting livestock and wildlife. The structures of FolM alternative dihydrofolate reductases 1 from Brucella suis and Brucella canis were determined and reported in this study. These enzymes show high sequence similarity to each other but low sequence identity with other structurally known homologues. The structures resemble NADPH-dependent short-chain reductases and share their highest tertiary structural similarity with protozoan pteridine reductases.
ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS
(2022)
Article
Biochemical Research Methods
Dylan K. Beard, Seonna Bristol, Kayla Cosby, Amber Davis, Courtney Manning, Lionel Perry, Lauren Snapp, Arian Toy, Kayla Wheeler, Jeremy Young, Bart Staker, Tracy L. Arakaki, Jan Abendroth, Sandhya Subrahamanian, Thomas E. Edwards, Peter J. Myler, Oluwatoyin A. Asojo
Summary: Giardiasis is the most prevalent diarrheal disease globally, affecting both humans and animals, particularly in developing countries, travelers, and HIV-infected individuals. Treatment involves antibiotics like tinidazole and metronidazole, with ongoing research focusing on characterizing the proteins of Giardia lamblia to develop new therapeutics. This study presents the atomic resolution structure of a 15.6 kDa protein from Giardia lamblia, providing insights into potential targets for drug development.
ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS
(2022)
Article
Biochemical Research Methods
Dylan K. Beard, Sandhya Subramanian, Jan Abendroth, David M. Dranow, Thomas E. Edwards, Peter J. Myler, Oluwatoyin A. Asojo
Summary: This study reports the crystal structures of the potential drug target BADH from B. pseudomallei. Structural comparison revealed similarities to BADH from Pseudomonas aeruginosa, which could facilitate drug-repurposing studies for B. pseudomallei.
ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS
(2022)
Article
Biochemical Research Methods
Jasmine Maddy, Bart L. Staker, Sandhya Subramanian, Jan Abendroth, Thomas E. Edwards, Peter J. Myler, Kevin Hybiske, Oluwatoyin A. Asojo
Summary: Chlamydia trachomatis is a leading cause of bacterial sexually transmitted infections worldwide and a common infection in the United States. The development of new therapeutics is necessary due to drug resistance and the failure of current treatments to clear persistent infections. The Seattle Structural Genomics Center for Infectious Disease has determined the structures of potential drug targets for C. trachomatis, including the inorganic pyrophosphatase. The crystal structure of the inorganic pyrophosphatase reveals shared features that could aid in the repurposing of inhibitors for new therapeutics.
ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS
(2022)
Article
Public, Environmental & Occupational Health
Rebekah W. Moehring, Angelina Davis, Elizabeth Dodds Ashley, April P. Dyer, Richard H. Drew, Yuliya Loknyghina, Melissa D. Johnson, Travis M. Jones, S. Shaefer Spires, Daniel J. Sexton, Deverick J. Anderson
Summary: Policies promoting converting antibiotics from intravenous to oral administration are crucial for hospital antimicrobial stewardship programs, and developing metrics and comparison methods can help improve implementation.
INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY
(2023)
Article
Multidisciplinary Sciences
Bin Xie, Allison Maker, Andrew Priest, David M. Dranow, Jenny N. Phan, Thomas E. Edwards, Bart L. Staker, Peter J. Myler, Barry M. Gumbiner, Sanjeevi Sivasankar
Summary: The monoclonal antibody 19A11 can interact with Ecad in two distinct modes, one of which enhances the adhesion of Ecad. Adhesion is strengthened by the formation of a salt bridge.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Allergy
Bruce L. Zuraw, Marcus Maurer, Daniel J. Sexton, Marco Cicardi
Summary: Monoclonal antibodies (mAbs) have shown efficacy and safety in various therapeutic areas. This article discusses the advantages and limitations of mAbs compared to small molecules and introduces a novel mAb for the treatment of hereditary angioedema (HAE), a rare and life-threatening condition characterized by recurrent swelling attacks. Lanadelumab, a fully human mAb targeting plasma kallikrein, has demonstrated promising results in clinical trials, including a pivotal Phase 3 study. It has the potential to provide an effective and less burdensome treatment option for HAE patients.
ALLERGOLOGY INTERNATIONAL
(2023)
Article
Chemistry, Medicinal
Helen Haixia Wu, Maureen Crames, Yangjie Wei, Dongmei Liu, Kristina Gueneva-Boucheva, Ikbae Son, Lee Frego, Fei Han, Rachel Kroe-Barrett, Andrew Nixon, Michael Marlow
Summary: Monoclonal antibodies, especially IgGs and Ig-based molecules, are widely used biotherapeutic drugs. The engineering of the Fc domain of these drugs to optimize their interactions with Fc gamma receptors (FcgRs) has been extensively studied in recent years. However, limited information is available regarding the effects of mutations and isotype differences on the physicochemical properties and manufacturability of these drugs. This study systematically characterizes the effects of mutations and IgG4 isotype on the stability and manufacturability of six Fc variants, providing a basis for selecting appropriate Fc regions and predicting the impact of mutations on the drug development process.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2022)
Article
Chemistry, Medicinal
Mattheo Alcaraz, Francoise Roquet-Baneres, Stephen Adonai Leon-Icaza, Jan Abendroth, Yves-Marie Boudehen, Celine Cougoule, Thomas E. Edwards, Laurent Kremer
Summary: There is a significant medical need for effective treatments against Mycobacterium abscessus pulmonary infections, especially in cystic fibrosis (CF) patients. In this study, the antitubercular drug NITD-916 was found to have low minimum inhibitory concentration (MIC) values against M. abscessus in vitro, and it significantly reduced bacterial burden in human macrophages. Furthermore, NITD-916 treatment decreased the number and size of intracellular mycobacterial cords, indicating its potential in treating this difficult-to-treat mycobacterium. The study also confirmed that NITD-916 directly targets InhA(MAB) without activation requirements.
ACS INFECTIOUS DISEASES
(2022)
Review
Infectious Diseases
Mattheo Alcaraz, Thomas E. Edwards, Laurent Kremer
Summary: The treatment options for Mycobacterium abscessus infections are limited. The authors review the potential drug targets in M. abscessus related to the mycolic acid biosynthetic pathway and discuss the activity of inhibitors targeting MmpL3 and InhA. They highlight the potential of NITD-916 as a direct InhA inhibitor for the treatment of multidrug resistant M. abscessus infections.
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY
(2023)
Article
Biochemical Research Methods
Julia Moorefield, Yagmur Konuk, Jordan O. Norman, Jan Abendroth, Thomas E. Edwards, Donald D. Lorimer, Stephen J. Mayclin, Bart L. Staker, Justin K. Craig, Kayleigh F. Barett, Lynn K. Barrett, Wesley C. Van Voorhis, Peter J. Myler, Krystle J. McLaughlin
Summary: Inorganic pyrophosphatases hydrolyze the byproduct PPi and prevent its accumulation in cells, while providing orthophosphates P-i for biosynthetic pathways. L. pneumophila PPase demonstrates hydrolytic activity with Mg2+ as the preferred metal cofactor for catalysis.
ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Sneha Basak, Yong Li, Suyuan Tao, Fereidoon Daryaee, Jonathan Merino, Chendi Gu, Silvia L. Delker, Jenny N. Phan, Thomas E. Edwards, Stephen G. Walker, Peter J. Tonge
Summary: UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a potential drug target in Gram-negative bacteria, and the residence time of inhibitors on this target is found to be correlated with their post-antibiotic effect. The study also demonstrates that an analogue has a longer residence time and post-antibiotic effect, providing a platform for rational modulation of inhibitor residence time and the development of antibacterial agents.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Allison Maker, Madison Bolejack, Leslayann Schecterson, Brad Hammerson, Jan Abendroth, Thomas E. Edwards, Bart Staker, Peter J. Myler, Barry M. Gumbiner
Summary: This study utilizes cryo-electron microscopy (EM) and X-ray crystallography to investigate the regulation of E-cadherin adhesion on cell surface. Novel dimer conformations were observed in solution through cryo-EM, and activating antibodies were used to alter the adhesive dimer state. The structures of activating Fabs bound to E-cadherin reveal new insights into the regulation of cell adhesion.