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Current Medicinal Chemistry.... Sep 2003Specific radioprotection of normal tissue represents a promising approach to improve radiotherapy. The ultimate feature of a normal tissue selective radioprotector is... (Review)
Review
Specific radioprotection of normal tissue represents a promising approach to improve radiotherapy. The ultimate feature of a normal tissue selective radioprotector is that tumor tissue is excluded from protection. Radioprotectors of the current generation, such as Ethyol, are not explicit normal tissue specific. In contrast, the Bowman Birk protease inhibitor, which is known to prevent in vitro and in vivo radiation-induced carcinogenesis, was found to be normal tissue specific. Moreover, the molecular restrictions for this specificity were identified. The radioprotective effect is dependent upon the presence of a functional wt. TP53. Since a high amount of tumors have lost TP53 function during tumor development, the clinical application of BBI to protect normal tissue from radiation damage would effectively improve the therapeutic outcome of radiation therapy. We succeeded to identify stimulation of DNA-repair mechanisms, such as nucleotide excision repair (NER) and nonhomologous end joining (NHEJ), as molecular mode of action. These results are in good agreement with the observations that BBI concomitantly exhibits anticarcinogenic effect and radioprotective effects. Taken together, BBI is recommended as a radioprotector for normal tissue expressing wild type TP53 during treatment of tumors characterized by a mutant TP53.
Topics: Animals; Fibroblasts; Humans; Neoplasms; Protease Inhibitors; Radiation-Protective Agents; Trypsin Inhibitor, Bowman-Birk Soybean; Tumor Suppressor Protein p53
PubMed: 12871082
DOI: 10.2174/1568011033482288 -
Proceedings of the National Academy of... Dec 2011Hepatitis C virus (HCV) infection is a global health burden with over 170 million people infected worldwide. In a significant portion of patients chronic hepatitis C...
Hepatitis C virus (HCV) infection is a global health burden with over 170 million people infected worldwide. In a significant portion of patients chronic hepatitis C infection leads to serious liver diseases, including fibrosis, cirrhosis, and hepatocellular carcinoma. The HCV NS3 protein is essential for viral polyprotein processing and RNA replication and hence viral replication. It is composed of an N-terminal serine protease domain and a C-terminal helicase/NTPase domain. For full activity, the protease requires the NS4A protein as a cofactor. HCV NS3/4A protease is a prime target for developing direct-acting antiviral agents. First-generation NS3/4A protease inhibitors have recently been introduced into clinical practice, markedly changing HCV treatment options. To date, crystal structures of HCV NS3/4A protease inhibitors have only been reported in complex with the protease domain alone. Here, we present a unique structure of an inhibitor bound to the full-length, bifunctional protease-helicase NS3/4A and show that parts of the P4 capping and P2 moieties of the inhibitor interact with both protease and helicase residues. The structure sheds light on inhibitor binding to the more physiologically relevant form of the enzyme and supports exploring inhibitor-helicase interactions in the design of the next generation of HCV NS3/4A protease inhibitors. In addition, small angle X-ray scattering confirmed the observed protease-helicase domain assembly in solution.
Topics: Carrier Proteins; Chromatography, Gel; Crystallization; Crystallography, X-Ray; Escherichia coli; Hepatitis C; Inhibitory Concentration 50; Intracellular Signaling Peptides and Proteins; Models, Molecular; Protease Inhibitors; Protein Conformation; Scattering, Small Angle; Viral Nonstructural Proteins
PubMed: 22160684
DOI: 10.1073/pnas.1110534108 -
Biomedicine & Pharmacotherapy =... Feb 2017Cancer is the second cause of death in 2015, and it has been estimated to surpass heart diseases as the leading cause of death in the next few years. Several mechanisms... (Review)
Review
Cancer is the second cause of death in 2015, and it has been estimated to surpass heart diseases as the leading cause of death in the next few years. Several mechanisms are involved in cancer pathogenesis. Studies have indicated that proteases are also implicated in tumor growth and progression which is highly dependent on nutrient and oxygen supply. On the other hand, protease inhibitors could be considered as a potent strategy in cancer therapy. On the basis of the type of the key amino acid in the active site of the protease and the mechanism of peptide bond cleavage, proteases can be classified into six groups: cysteine, serine, threonine, glutamic acid, aspartate proteases, as well as matrix metalloproteases. In this review, we focus on the role of different types of proteases and protease inhibitors in cancer pathogenesis.
Topics: Animals; Antineoplastic Agents; Carcinogenesis; Humans; Neoplasms; Peptide Hydrolases; Protease Inhibitors; Protein Structure, Secondary; Treatment Outcome
PubMed: 28006747
DOI: 10.1016/j.biopha.2016.12.021 -
Pharmacology & Therapeutics Jun 1998Certain protease inhibitors, called the anticarcinogenic protease inhibitors in this review, are capable of preventing carcinogenesis in a wide variety of in vivo and in... (Review)
Review
Certain protease inhibitors, called the anticarcinogenic protease inhibitors in this review, are capable of preventing carcinogenesis in a wide variety of in vivo and in vitro model systems. The anticarcinogenic protease inhibitors are extremely potent agents with the ability to prevent cancer, with some unique characteristics as anticarcinogenic agents. The anticarcinogenic protease inhibitors have the ability to irreversibly suppress the carcinogenic process. They do not have to be continuously present to suppress carcinogenesis. They can be effective when applied in both in vivo and in vitro carcinogenesis assay systems at long time periods after carcinogen exposure, and are effective as anticarcinogenic agents at extremely low molar concentrations. While several different types of protease inhibitors can prevent the carcinogenic process, the most potent of the anticarcinogenic protease inhibitors on a molar basis are those with the ability to inhibit chymotrypsin or chymotrypsin-like proteases. The soybean-derived protease inhibitor, Bowman-Birk inhibitor (BBI), is a potent chymotrypsin inhibitor that has been extensively studied for its ability to prevent carcinogenesis in many different model systems. Much of this review is focused on the characteristics of BBI as the anticarcinogenic protease inhibitor, as this is the protease inhibitor that has risen to the human trial stage as a human cancer chemopreventive agent. Part of this review hypothesizes that the Bowman-Birk family of protease inhibitors plays a role in plants similar to that of alpha1-antichymotrypsin in people. Both BBI and alpha1-antichymotrypsin are potent inhibitors of chymotrypsin and chymotrypsin-like enzymes, are highly anti-inflammatory, and are thought to play important roles in the defense of their respective organisms. It is believed that BBI will be shown to play a major role in the prevention and/or treatment of several different diseases, in addition to cancer.
Topics: Antineoplastic Agents; Carcinogenicity Tests; Humans; Inflammation; Protease Inhibitors; Trypsin Inhibitor, Bowman-Birk Soybean
PubMed: 9690817
DOI: 10.1016/s0163-7258(98)00010-2 -
International Journal of Molecular... Jun 2009Antimicrobial proteins (peptides) are known to play important roles in the innate host defense mechanisms of most living organisms, including plants, insects, amphibians... (Review)
Review
Antimicrobial proteins (peptides) are known to play important roles in the innate host defense mechanisms of most living organisms, including plants, insects, amphibians and mammals. They are also known to possess potent antibiotic activity against bacteria, fungi, and even certain viruses. Recently, the rapid emergence of microbial pathogens that are resistant to currently available antibiotics has triggered considerable interest in the isolation and investigation of the mode of action of antimicrobial proteins (peptides). Plants produce a variety of proteins (peptides) that are involved in the defense against pathogens and invading organisms, including ribosome-inactivating proteins, lectins, protease inhibitors and antifungal peptides (proteins). Specially, the protease inhibitors can inhibit aspartic, serine and cysteine proteinases. Increased levels of trypsin and chymotrypsin inhibitors correlated with the plants resistance to the pathogen. Usually, the purification of antimicrobial proteins (peptides) with protease inhibitor activity was accomplished by salt-extraction, ultrafiltration and C(18) reverse phase chromatography, successfully. We discuss the relation between antimicrobial and anti-protease activity in this review. Protease inhibitors from plants potently inhibited the growth of a variety of pathogenic bacterial and fungal strains and are therefore excellent candidates for use as the lead compounds for the development of novel antimicrobial agents.
Topics: Anti-Infective Agents; Bacteria; Candida albicans; Fabaceae; Peptides; Plants; Protease Inhibitors; Solanum tuberosum
PubMed: 19582234
DOI: 10.3390/ijms10062860 -
Protein and Peptide Letters 2015Ageing and skin exposure to UV radiation induces production and activation of matrix metalloproteinases (MMPs) and human neutrophil elastase (HNE). These enzymes are...
Ageing and skin exposure to UV radiation induces production and activation of matrix metalloproteinases (MMPs) and human neutrophil elastase (HNE). These enzymes are known to break down the extracellular matrix (ECM) which leads to wrinkle formation. Here, we demonstrated the potential of a solid-in-oil nanodispersion containing a competitive inhibitor peptide of HNE mixed with hyaluronic acid (HA), displaying 158 nm of mean diameter, to protect the skin against the ageing effects. Western blot analysis demonstrated that activation of MMP-1 in fibroblasts by HNE treatment is inhibited by the solid-in-oil nanodispersion containing the peptide and HA. The results clearly demonstrate that solid-in-oil nanodispersion containing the HNE inhibitor peptide is a promising strategy for anti-ageing effects. This effect can be seen particularly by ECM regulation by affecting fibroblasts. The formulation also enhances the formation of thicker bundles of actin filaments.
Topics: Animals; Cells, Cultured; Humans; Hyaluronic Acid; Models, Biological; Nanoparticles; Pancreatic Elastase; Peptides; Protease Inhibitors; Skin; Skin Aging; Swine
PubMed: 26343064
DOI: 10.2174/0929866522666150907111351 -
Biology of the Neonate 1982The total trypsin inhibiting capacity (TIC), and the content of the individual protease inhibitors, both the specific colostrum protease inhibitor (SCTI) and the...
The total trypsin inhibiting capacity (TIC), and the content of the individual protease inhibitors, both the specific colostrum protease inhibitor (SCTI) and the serum-type inhibitors, i.e., alpha 2-macroglobulin f and s, inter-alpha-trypsin inhibitor, alpha 2-antitrypsin and alpha 1-protease inhibitor, were quantified in porcine mammary secretions throughout lactation using immunoprecipitation methods. In addition, albumin, of serum origin, and beta-lactoglobulin, a milk-specific protein, were quantified and used as references. In presuckled colostrum, high levels of TIC, SCTI, albumin and beta-lactoglobulin were found, while the serum-type inhibitors appeared in amounts related to their molecular weights ranging from 3-6% of the adult serum levels for the macroglobulins to 42% for alpha 1-protease inhibitor. These parameters all decreased during lactation. The levels of TIC and SCTI especially decreased during the first days of lactation, and SCTI disappeared from milk after 5-7 days. Mature milk showed low TIC levels, about 0.1 IU/ml, which originated from the low amounts of the serum-type inhibitors (1-4% of the adult serum level). The levels of both alpha 2-macroglobulin f and s decreased less than albumin did in sow milk, while the other inhibitors decreased more or on the same order as albumin. A considerable variation in the amounts of the protease inhibitors between individuals and also between different teat secretions of the same sow, especially in colostrum, was evident. The possible physiological functions of the protease inhibitors in the mammary gland of the sow and in the gastrointestinal tract of her nursing offspring are discussed.
Topics: Albumins; Animals; Animals, Suckling; Colostrum; Female; Lactation; Mammary Glands, Animal; Milk; Pregnancy; Protease Inhibitors; Swine; Trypsin Inhibitors; alpha-Macroglobulins
PubMed: 6182928
DOI: 10.1159/000241597 -
Bioorganic & Medicinal Chemistry Apr 2014The effects of additional substituents covering the prime-site of retro-inverso (RI)-modified HTLV-1 protease inhibitors containing a hydroxyethylamine isoster were...
The effects of additional substituents covering the prime-site of retro-inverso (RI)-modified HTLV-1 protease inhibitors containing a hydroxyethylamine isoster were clarified. Stereo-selective construction of the most potent isoster backbone was achieved by the Evans-aldol reaction. Addition of N-acetylated d-amino acid corresponding to the P2' site gave an RI-modified inhibitor showing superior inhibitory activity to the previous inhibitor. Inhibitory activities of the newly synthesized inhibitors suggest that partially modified RI inhibitors would interact with HTLV-1 protease in the same manner as the parent hydroxyethylamine inhibitor.
Topics: Amino Acid Sequence; Aspartic Acid Endopeptidases; Ethylamines; Human T-lymphotropic virus 1; Humans; Protease Inhibitors; Protein Binding
PubMed: 24680060
DOI: 10.1016/j.bmc.2014.02.050 -
Journal of Biomolecular Structure &... Nov 2020Zika virus (ZIKV) is an emerging mosquito-borne flavivirus and infection by ZIKV Asian lineage is known to cause fetal brain anomalies and Guillain-Barrés syndrome. The...
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus and infection by ZIKV Asian lineage is known to cause fetal brain anomalies and Guillain-Barrés syndrome. The WHO declared ZIKV a global public health emergency in 2016. However, currently neither vaccines nor antiviral prophylaxis/treatments are available. In this study, we report the identification of a C2-symmetric diol-based Human immunodeficiency virus type-1 (HIV) protease inhibitor active against ZIKV NS2B-NS3 protease. The compound, referred to as , was identified by screening of a library of 6265 protease inhibitors. Molecular dynamics (MD) simulation studies revealed that compound formed a stable complex with ZIKV protease. Interaction analysis of compound 's binding pose from the cluster analysis of MD simulations trajectories predicted that mostly interacted with ZIKV NS3. Although designed as an aspartyl protease inhibitor, compound was found to inhibit ZIKV serine protease with IC = 143.25 ± 5.45 µM, in line with the results. Additionally, linear interaction energy method (LIE) was used to estimate binding affinities of compounds and (a known panflavivirus peptide hybrid with IC = 1.64 ± 0.015 µM against ZIKV protease). The LIE method correctly predicted the binding affinity of compound to be lower than that of , proving to be superior to the molecular docking methods in scoring and ranking compounds. Since most of the reported ZIKV protease inhibitors are positively charged peptide-hybrids, with our without electrophilic warheads, compound represents a less polar and more drug-like non-peptide hit compound useful for further optimization.Communicated by Ramaswamy Sarma.
Topics: Animals; Antiviral Agents; HIV; Human Immunodeficiency Virus Proteins; Humans; Molecular Docking Simulation; Protease Inhibitors; Viral Nonstructural Proteins; Zika Virus; Zika Virus Infection
PubMed: 31880199
DOI: 10.1080/07391102.2019.1704882 -
Drugs Jun 2024Ensitrelvir fumaric acid (Xocova) is an oral SARS-CoV-2 main protease inhibitor developed by Shionogi for the treatment of SARS-CoV-2 infection. It is the first... (Review)
Review
Ensitrelvir fumaric acid (Xocova) is an oral SARS-CoV-2 main protease inhibitor developed by Shionogi for the treatment of SARS-CoV-2 infection. It is the first single-entity, nonpeptidic, noncovalent, small molecule antiviral of its kind. Following emergency regulatory approval in Japan in November 2022, ensitrelvir received standard approval in Japan on 5 March 2024 for the treatment of SARS-CoV-2 infection. This article summarizes the milestones in the development of ensitrelvir leading to this first standard approval for SARS-CoV-2 infection.
Topics: Humans; Drug Approval; COVID-19 Drug Treatment; Antiviral Agents; SARS-CoV-2; Japan; Fumarates; Protease Inhibitors; Indazoles; Triazines; Triazoles
PubMed: 38795314
DOI: 10.1007/s40265-024-02039-y