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International Journal of Molecular... Apr 2023Gastroesophageal reflux disease (GERD) significantly impacts patient quality of life and is a major risk factor for the development of Barrett's esophagus (BE) and...
Gastroesophageal reflux disease (GERD) significantly impacts patient quality of life and is a major risk factor for the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Proton pump inhibitors (PPIs) are the standard-of-care for GERD and are among the most prescribed drugs in the world, but do not protect against nonacid components of reflux such as pepsin, or prevent reflux-associated carcinogenesis. We recently identified an HIV protease inhibitor amprenavir that inhibits pepsin and demonstrated the antireflux therapeutic potential of its prodrug fosamprenavir in a mouse model of laryngopharyngeal reflux. In this study, we assessed the capacity of amprenavir to protect against esophageal epithelial barrier disruption in vitro and related molecular events, E-cadherin cleavage, and matrix metalloproteinase induction, which are associated with GERD severity and esophageal cancer. Herein, weakly acidified pepsin (though not acid alone) caused cell dissociation accompanied by regulated intramembrane proteolysis of E-cadherin. Soluble E-cadherin responsive matrix metalloproteinases (MMPs) were transcriptionally upregulated 24 h post-treatment. Amprenavir, at serum concentrations achievable given the manufacturer-recommended dose of fosamprenavir, protected against pepsin-induced cell dissociation, E-cadherin cleavage, and MMP induction. These results support a potential therapeutic role for amprenavir in GERD recalcitrant to PPI therapy and for preventing GERD-associated neoplastic changes.
Topics: Animals; Mice; Pepsin A; Protease Inhibitors; Quality of Life; Esophageal Neoplasms; Enzyme Inhibitors; Laryngopharyngeal Reflux; Proton Pump Inhibitors
PubMed: 37047737
DOI: 10.3390/ijms24076765 -
Biomedicine & Pharmacotherapy =... Feb 2022Four types of antifungal drugs are available that include inhibitors of ergosterol synthesis, of fungal RNA biosynthesis, and of cell wall biosynthesis as well as... (Review)
Review
Four types of antifungal drugs are available that include inhibitors of ergosterol synthesis, of fungal RNA biosynthesis, and of cell wall biosynthesis as well as physiochemical regulators of fungal membrane sterols. Increasing resistance to antifungal drugs can severely limit treatment options of fungal nail infections, vaginal candidiasis, ringworm, blastomycosis, histoplasmosis, and Candida infections of the mouth, throat, and esophagus, among other infections. Development of strategies focused on new fungicides can effectively help tackle troublesome fungal diseases. The virulence and optimal growth of fungi depend on various extracellular secreted factors, among which proteases, such as serine proteases, are of particular interest. A specific extracellular proteolytic system enables fungi to survive and penetrate the tissues. Given the role of fungal proteases in infection, any molecule capable of selectively and specifically inhibiting their activity can lead to the development of potential drugs. Owing to their specific mode of action, fungal protease inhibitors can avoid fungal resistance observed with currently available treatments. Although fungal secreted proteases have been extensively studied as potential virulence factors, our understanding of the substrate specificity of such proteases remains poor. In this review, we summarize the recent advances in the design and development of specific serine protease inhibitors and provide a brief history of the compounds that inhibit fungal serine protease activity.
Topics: Antifungal Agents; Fungi; Humans; Mycoses; Serine Proteases; Serine Proteinase Inhibitors
PubMed: 34902742
DOI: 10.1016/j.biopha.2021.112523 -
International Journal of Molecular... Dec 2023Chronic rhinosinusitis (CRS) is an inflammation of the nasal and paranasal sinus mucosa, and eosinophilic CRS (eCRS) is a subtype characterized by significant eosinophil... (Review)
Review
Chronic rhinosinusitis (CRS) is an inflammation of the nasal and paranasal sinus mucosa, and eosinophilic CRS (eCRS) is a subtype characterized by significant eosinophil infiltration and immune response by T-helper-2 cells. The pathogenesis of eCRS is heterogeneous and involves various environmental and host factors. Proteases from external sources, such as mites, fungi, and bacteria, have been implicated in inducing type 2 inflammatory reactions. The balance between these proteases and endogenous protease inhibitors (EPIs) is considered important, and their imbalance can potentially lead to type 2 inflammatory reactions, such as eCRS. In this review, we discuss various mechanisms by which exogenous proteases influence eCRS and highlight the emerging role of endogenous protease inhibitors in eCRS pathogenesis.
Topics: Humans; Rhinitis; Peptide Hydrolases; Rhinosinusitis; Sinusitis; Chronic Disease; Endopeptidases; Protease Inhibitors; Hypersensitivity; Eosinophils
PubMed: 38139201
DOI: 10.3390/ijms242417372 -
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 -
Antiviral Research Feb 2024Since the start of the SARS-CoV-2 pandemic, the search for antiviral therapies has been at the forefront of medical research. To date, the 3CLpro inhibitor nirmatrelvir...
Since the start of the SARS-CoV-2 pandemic, the search for antiviral therapies has been at the forefront of medical research. To date, the 3CLpro inhibitor nirmatrelvir (Paxlovid®) has shown the best results in clinical trials and the greatest robustness against variants. A second SARS-CoV-2 protease inhibitor, ensitrelvir (Xocova®), has been developed. Ensitrelvir, currently in Phase 3, was approved in Japan under the emergency regulatory approval procedure in November 2022, and is available since March 31, 2023. One of the limitations for the use of antiviral monotherapies is the emergence of resistance mutations. Here, we experimentally generated mutants resistant to nirmatrelvir and ensitrelvir in vitro following repeating passages of SARS-CoV-2 in the presence of both antivirals. For both molecules, we demonstrated a loss of sensitivity for resistance mutants in vitro. Using a Syrian golden hamster infection model, we showed that the ensitrelvir M49L mutation, in the multi-passage strain, confers a high level of in vivo resistance. Finally, we identified a recent increase in the prevalence of M49L-carrying sequences, which appears to be associated with multiple repeated emergence events in Japan and may be related to the use of Xocova® in the country since November 2022. These results highlight the strategic importance of genetic monitoring of circulating SARS-CoV-2 strains to ensure that treatments administered retain their full effectiveness.
Topics: Animals; Cricetinae; Protease Inhibitors; SARS-CoV-2; COVID-19; Enzyme Inhibitors; Anti-Infective Agents; Antiviral Agents; Mesocricetus
PubMed: 38272321
DOI: 10.1016/j.antiviral.2024.105814 -
Expert Opinion on Pharmacotherapy Dec 2022First-generation therapeutics have improved clinical outcomes in patients infected with SARS-CoV-2. However, viral evolution has produced variants and subvariants...
INTRODUCTION
First-generation therapeutics have improved clinical outcomes in patients infected with SARS-CoV-2. However, viral evolution has produced variants and subvariants capable of resisting many of these drugs and novel treatment strategies are urgently needed.
AREAS COVERED
A corporate compound library screen identified ensitrelvir (formerly S-217622), a non-covalent, non-peptidic, orally bioavailable small-molecule protease inhibitor as a potential treatment for SARS-CoV-2. Ensitrelvir cleaves the active site of the 3C-like protease (3CL), which is conserved across SARS-CoV-2 variants and subvariants, with no human cell protease with similar specificity.
EXPERT OPINION
Ensitrelvir demonstrates strong antiviral activity against the SARS-CoV-2 Omicron subvariants BA.4 and BA.5, which have driven new waves of infection throughout 2022, suggesting a potential therapeutic option for patients with COVID-19. This manuscript reviews what is known about ensitrelvir and explores how this drug may be used in the future to address the SARS-CoV-2 pandemic.
Topics: Humans; SARS-CoV-2; Viral Nonstructural Proteins; Cysteine Endopeptidases; Protease Inhibitors; Antiviral Agents; COVID-19 Drug Treatment
PubMed: 36350029
DOI: 10.1080/14656566.2022.2146493 -
Expert Opinion on Pharmacotherapy Feb 2024Simnotrelvir is a selective 3-chymotrypsin-like oral protease inhibitor with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). (Review)
Review
INTRODUCTION
Simnotrelvir is a selective 3-chymotrypsin-like oral protease inhibitor with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
AREAS COVERED
On 18 January 2024, results of a double-blind, randomized, placebo-controlled trial of simnotrelvir as a treatment for mild-to moderate COVID-19-were published, indicating the drug, when given in combination with ritonavir, shortened the time to resolution of symptoms.
EXPERT OPINION
Treatment options for most outpatients with mild-to-moderate COVID-19 are limited. The protease inhibitor nirmatrelvir in combination with ritonavir has proven effective in patients who are high risk for progression to severe COVID-19, but there are no approved therapies for standard-risk patients, who now comprise the majority of the population. Simnotrelvir appears to be effective in standard-risk patients, including those who have completed primary vaccination against COVID-19 and have received a booster dose. This manuscript examines the rationale for the development of simnotrelvir and explores how this drug may be used in the future to treat COVID-19.
Topics: Humans; COVID-19 Drug Treatment; Antiviral Agents; COVID-19; SARS-CoV-2; Ritonavir; Protease Inhibitors; Randomized Controlled Trials as Topic; Drug Therapy, Combination
PubMed: 38393345
DOI: 10.1080/14656566.2024.2323597 -
Journal of Medicinal Chemistry Jun 2022SARS-CoV-2 is the causative agent of the COVID-19 pandemic. The approval of vaccines and small-molecule antivirals is vital in combating the pandemic. The viral... (Review)
Review
SARS-CoV-2 is the causative agent of the COVID-19 pandemic. The approval of vaccines and small-molecule antivirals is vital in combating the pandemic. The viral polymerase inhibitors remdesivir and molnupiravir and the viral main protease inhibitor nirmatrelvir/ritonavir have been approved by the U.S. FDA. However, the emergence of variants of concern/interest calls for additional antivirals with novel mechanisms of action. The SARS-CoV-2 papain-like protease (PL) mediates the cleavage of viral polyprotein and modulates the host's innate immune response upon viral infection, rendering it a promising antiviral drug target. This Perspective highlights major achievements in structure-based design and high-throughput screening of SARS-CoV-2 PL inhibitors since the beginning of the pandemic. Encouraging progress includes the design of non-covalent PL inhibitors with favorable pharmacokinetic properties and the first-in-class covalent PL inhibitors. In addition, we offer our opinion on the knowledge gaps that need to be filled to advance PL inhibitors to the clinic.
Topics: Antiviral Agents; Coronavirus Papain-Like Proteases; Humans; Pandemics; Protease Inhibitors; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35620927
DOI: 10.1021/acs.jmedchem.2c00303 -
International Journal of Biological... Jan 2023Silkworm spins silk fibers to make the cocoon to protect the pupa from predators and pathogenic microbes. To understand the defense mechanism of the cocoon, many... (Review)
Review
Silkworm spins silk fibers to make the cocoon to protect the pupa from predators and pathogenic microbes. To understand the defense mechanism of the cocoon, many antimicrobial proteins are currently identified. The functionality of these proteins is studied, including protease inhibitors and seroins. Protease inhibitors are incredibly variable in sequences and domains, and most of them contain multiple pairs of disulfide bonds. Thereby they have stable structures and activities. Seroins have two motifs: the proline-rich N-terminal motif and the sequence conserved C-terminal motif. Protease inhibitors mainly play antifungal roles, whereas seroins have broad-spectrum antimicrobial activities against bacteria, fungi and viruses. These antimicrobial proteins show higher abundance in the sericin layers than in the fibroin layer and are more abundant in the outer cocoon layer than in the inner cocoon layer. Besides silk proteins, the silkworm cocoon also contains small amounts of non-protein antimicrobial components such as organic acids, alkaloids, flavonoids, and heterocyclic compounds. This review describes the extraction methods, expression pattern, microbiostatic mechanism, application fields and advantages of the antimicrobial components in the silkworm cocoon. The in-depth understanding of antimicrobial silk components will help us improve the processing technology of cocoons and expand the application fields of the cocoons.
Topics: Animals; Silk; Bombyx; Anti-Infective Agents; Sericins; Protease Inhibitors
PubMed: 36252626
DOI: 10.1016/j.ijbiomac.2022.10.103 -
Molecules (Basel, Switzerland) Apr 2022Since the outbreak of COVID-19, one of the strategies used to search for new drugs has been to find inhibitors of the main protease (Mpro) of the virus SARS-CoV-2.... (Review)
Review
Since the outbreak of COVID-19, one of the strategies used to search for new drugs has been to find inhibitors of the main protease (Mpro) of the virus SARS-CoV-2. Initially, previously reported inhibitors of related proteases such as the main proteases of SARS-CoV and MERS-CoV were tested. A huge effort was then carried out by the scientific community to design, synthesize and test new small molecules acting as inactivators of SARS-CoV-2 Mpro. From the chemical structure view, these compounds can be classified into two main groups: one corresponds to modified peptides displaying an adequate sequence for high affinity and a reactive warhead; and the second is a diverse group including chemical compounds that do not have a peptide framework. Although a drug including a SARS-CoV-2 main protease inhibitor has already been commercialized, denoting the importance of this field, more compounds have been demonstrated to be promising potent inhibitors as potential antiviral drugs.
Topics: Antiviral Agents; Coronavirus 3C Proteases; Humans; Molecular Docking Simulation; Peptide Hydrolases; Protease Inhibitors; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35458721
DOI: 10.3390/molecules27082523