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BioMed Research International 2022In this work, the discovery and description of PF-07321332, a major bioavailable oral SARS-CoV-2 protease inhibitor with in vitro human coronavirus antiviral activity,... (Review)
Review
In this work, the discovery and description of PF-07321332, a major bioavailable oral SARS-CoV-2 protease inhibitor with in vitro human coronavirus antiviral activity, and excellent selection of off-target and in vivo immune profiles are reported. Various drugs and novel compound candidates for the treatment of the COVID-19 pandemic have been developed. PF-07321332 (or nirmatrelvir) is a new oral antiviral drug developed by Pfizer. In response to the pandemic, Pfizer has developed the COVID vaccine and in 2022 will launch its new major anti-SARS-Cov-2 protease inhibitor (PI). The combination of ritonavir and nirmatrelvir is under study in phase III of the clinical trial with a brand name Paxlovid. Paxlovid is an active 3Cl protease inhibitor. Paxlovid exerts its antiviral efficacy by inhibiting a necessary protease in the viral replication procedure. Proteases of coronavirus cleave several sites in the viral polyprotein where pyrrolidone was replaced by flexible glutamine. Due to the coronavirus pandemic, there is high demand for synthesis and development of this novel drug. Herein, we report the synthetic route and the mechanism of action was recently published on nirmatrelvir. Also, a comparison of the performance of two new oral antiviruses (molnupiravir and nirmatrelvir) for the treatment of COVID-19 is described. This review will be helpful for different disciplines such as biochemistry, organic chemistry, medicinal chemistry, and pharmacology.
Topics: Antiviral Agents; COVID-19 Vaccines; Coronavirus 3C Proteases; Cysteine Endopeptidases; Drug Combinations; Humans; Lactams; Leucine; Nitriles; Pandemics; Proline; Protease Inhibitors; Ritonavir; SARS-CoV-2; Viral Nonstructural Proteins; COVID-19 Drug Treatment
PubMed: 35845944
DOI: 10.1155/2022/7341493 -
Science (New York, N.Y.) Apr 2020The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug...
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (M, also called 3CL) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 M and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 M The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.
Topics: Amides; Animals; Antiviral Agents; Betacoronavirus; Binding Sites; Cell Line, Tumor; Coronavirus 3C Proteases; Crystallography, X-Ray; Cysteine Endopeptidases; Drug Design; Half-Life; Humans; Lung; Mice; Models, Molecular; Protease Inhibitors; Protein Domains; Protein Multimerization; Pyridones; SARS-CoV-2; Viral Nonstructural Proteins; Virus Replication
PubMed: 32198291
DOI: 10.1126/science.abb3405 -
Nature Immunology Oct 2023Glioblastoma (GBM) tumors consist of multiple cell populations, including self-renewing glioblastoma stem cells (GSCs) and immunosuppressive microglia. Here we...
Glioblastoma (GBM) tumors consist of multiple cell populations, including self-renewing glioblastoma stem cells (GSCs) and immunosuppressive microglia. Here we identified Kunitz-type protease inhibitor TFPI2 as a critical factor connecting these cell populations and their associated GBM hallmarks of stemness and immunosuppression. TFPI2 promotes GSC self-renewal and tumor growth via activation of the c-Jun N-terminal kinase-signal transducer and activator of transcription (STAT)3 pathway. Secreted TFPI2 interacts with its functional receptor CD51 on microglia to trigger the infiltration and immunosuppressive polarization of microglia through activation of STAT6 signaling. Inhibition of the TFPI2-CD51-STAT6 signaling axis activates T cells and synergizes with anti-PD1 therapy in GBM mouse models. In human GBM, TFPI2 correlates positively with stemness, microglia abundance, immunosuppression and poor prognosis. Our study identifies a function for TFPI2 and supports therapeutic targeting of TFPI2 as an effective strategy for GBM.
Topics: Animals; Mice; Humans; Glioblastoma; Protease Inhibitors; Tumor Microenvironment; Signal Transduction; Carrier Proteins; Immunosuppressive Agents; Cell Line, Tumor; Neoplastic Stem Cells
PubMed: 37667051
DOI: 10.1038/s41590-023-01605-y -
Journal of Medicinal Chemistry May 2022The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and...
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of , the first oral noncovalent, nonpeptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug design strategy. exhibited antiviral activity against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles for once-daily oral dosing. Furthermore, dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel noncovalent inhibitor could be a potential oral agent for treating COVID-19.
Topics: Animals; Antiviral Agents; COVID-19 Vaccines; Coronavirus 3C Proteases; Humans; Mice; Protease Inhibitors; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35352927
DOI: 10.1021/acs.jmedchem.2c00117 -
Profiles of Drug Substances,... 2021Darunavir: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-4-{[(4-aminophenyl)sulfonyl] (isobutyl)amino}-3-hydroxy-1-phenyl-2-butanyl]carbamate is a synthetic... (Review)
Review
Darunavir: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-4-{[(4-aminophenyl)sulfonyl] (isobutyl)amino}-3-hydroxy-1-phenyl-2-butanyl]carbamate is a synthetic non-peptide protease inhibitor. On June 2006, it was first approved by the Food and Drug administration (FDA) for treatment of resistant type-1 of the human immunodeficiency virus (HIV). In July 2016, the FDA expanded the approval for use of darunavir in pregnant women with HIV infection. Darunavir prevents the replication of HIV virus by inhibiting the catalytic activity of the HIV-1 protease enzyme, and selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus-infected cells, which prevents the formation of mature infectious virus particles. Darunavir is unique among currently available protease inhibitors because it maintains antiretroviral activity against a variety of multidrug-resistant HIV strains. This article discusses, by a critical extensive review of the literature, the description of darunavir in terms of its names, formulae, elemental composition, appearance, and use in the treatment of HIV-infected patients. The article also discusses the methods for preparation of darunavir, its physical-chemical properties, analytical methods for its determination, pharmacological properties, and dosing information.
Topics: Darunavir; Drug Resistance, Viral; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Pregnancy; United States
PubMed: 33461696
DOI: 10.1016/bs.podrm.2020.07.001 -
Nature Communications Oct 2023The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the...
The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the great demand for developing effective therapeutic agents. Here, we report the development of an orally bioavailable SARS-CoV-2 3C-like protease (3CL) inhibitor, namely simnotrelvir, and its preclinical evaluation, which lay the foundation for clinical trials studies as well as the conditional approval of simnotrelvir in combination with ritonavir for the treatment of COVID-19. The structure-based optimization of boceprevir, an approved HCV protease inhibitor, leads to identification of simnotrelvir that covalently inhibits SARS-CoV-2 3CL with an enthalpy-driven thermodynamic binding signature. Multiple enzymatic assays reveal that simnotrelvir is a potent pan-CoV 3CL inhibitor but has high selectivity. It effectively blocks replications of SARS-CoV-2 variants in cell-based assays and exhibits good pharmacokinetic and safety profiles in male and female rats and monkeys, leading to robust oral efficacy in a male mouse model of SARS-CoV-2 Delta infection in which it not only significantly reduces lung viral loads but also eliminates the virus from brains. The discovery of simnotrelvir thereby highlights the utility of structure-based development of marked protease inhibitors for providing a small molecule therapeutic effectively combatting human coronaviruses.
Topics: Mice; Female; Male; Animals; Humans; Rats; SARS-CoV-2; Protease Inhibitors; COVID-19; Antiviral Agents; Enzyme Inhibitors
PubMed: 37833261
DOI: 10.1038/s41467-023-42102-y -
International Journal of Radiation... 2023The purpose of the studies described in this mini review article was to identify nontoxic compounds that could prevent or suppress the radiation induced malignant... (Review)
Review
PURPOSE
The purpose of the studies described in this mini review article was to identify nontoxic compounds that could prevent or suppress the radiation induced malignant transformation of cells and be useful as human cancer preventive agents.
CONCLUSIONS
(1) Many different types of potential anticarcinogenic substances were evaluated initially for their abilities to prevent or suppress radiation induced malignant transformation in vitro, and certain anticarcinogenic protease inhibitors (APIs) were observed to be the most powerful anticarcinogenic agents at suppressing this surrogate endpoint biomarker of radiation carcinogenesis. (2) Within the category of APIs, those that inhibited the activity of chymotrypsin were effective at far lower molar concentrations than other APIs. The soybean-derived protease inhibitor known as the Bowman-Birk inhibitor (BBI) is a particularly powerful chymotrypsin inhibitor that is able to prevent radiation induced transformation in vitro (at concentrations down to nanomolar levels) as well as radiation induced carcinogenesis in vivo without toxicity. (3) There were many other unusual characteristics of APIs that led to the selection of one of these APIs, BBI, as the most appropriate compound for us to develop as a human cancer preventive agent. As one example, the APIs have an irreversible effect on carcinogenesis, while the effects are reversible for most anticarcinogenic agents when they are removed from carcinogenesis assay systems. (4) Numerous studies were performed in attempts to determine the potential mechanisms by which the APIs could prevent or suppress radiation induced carcinogenesis in in vitro and in vivo systems, and the results of these studies are described in this review article. The APIs and the proteases which interact with them appear to play important roles in radiation carcinogenesis. (5) Preparations for human trials using BBI began decades ago. The cost of preparing purified BBI was far too high to consider performing human trials with this agent, so BBI Concentrate (BBIC), a soybean extract enriched in BBI, was developed for the specific purpose of performing human trials with BBI. BBIC achieved Investigational New Drug (IND) Status with the Food and Drug Administration in April,1992, and human BBIC trials began at that time. (6) Several human trials were performed using BBIC and they indicated many potentially beneficial health effects produced by BBIC administration to people in various forms (e.g. tablets). 7) It is hypothesized that BBI takes the place of α-1-antichymotrypsin, an important regulatory compound in the human body, and helps to maintain homeostasis.
Topics: Humans; Protease Inhibitors; Trypsin Inhibitor, Bowman-Birk Soybean; Anticarcinogenic Agents; Peptide Hydrolases; Chymotrypsin; Cell Transformation, Neoplastic
PubMed: 34325613
DOI: 10.1080/09553002.2021.1962567 -
Biochimie Nov 2019Dozens of studies have assessed the practical value of plant cystatins as ectopic inhibitors of Cys proteases in biological systems. The potential of these proteins in... (Review)
Review
Dozens of studies have assessed the practical value of plant cystatins as ectopic inhibitors of Cys proteases in biological systems. The potential of these proteins in crop protection to control herbivorous pests and pathogens has been documented extensively over the past 25 years. Their usefulness to regulate endogenous Cys proteases in planta has also been considered recently, notably to implement novel traits of agronomic relevance in crops or to generate protease activity-depleted environments in plants or plant cells used as bioreactors for recombinant proteins. After a brief update on the basic structural characteristics of plant cystatins, we summarize recent advances on the use of these proteins in plant biotechnology. Attention is also paid to the molecular improvement of their structural properties for the improvement of their protease inhibitory effects or the fine-tuning of their biological target range.
Topics: Biotechnology; Cystatins; Cysteine Proteases; Cysteine Proteinase Inhibitors; Pest Control, Biological; Plant Proteins; Plants; Protein Engineering; Recombinant Proteins
PubMed: 31194996
DOI: 10.1016/j.biochi.2019.06.006 -
Expert Opinion on Investigational Drugs 2023Serine proteases are involved in many normal metabolic processes but also contribute to diseases of several organ systems, including viral and gastrointestinal diseases... (Review)
Review
INTRODUCTION
Serine proteases are involved in many normal metabolic processes but also contribute to diseases of several organ systems, including viral and gastrointestinal diseases and oncology. Upamostat is an orally bioavailable prodrug of WX-UK1, which is most active against trypsins and closely related enzymes.
AREAS COVERED
Research over the past two decades suggests several diseases in the three areas noted above which upamostat may be active. Upamostat has been studied clinically against several cancers and for outpatient treatment of COVID-19. Preclinical and clinical pharmacokinetic and metabolism studies demonstrate good bioavailability, sustained tissue levels, and high concentrations of the active moiety, WX-UK1, in stool, potentially important for treatment of gastrointestinal diseases. Clinical studies suggest activity against SARS-CoV-2; results against pancreatic cancer are also encouraging, though studies in both indications are not definitive. The drug was very well tolerated for periods of 2 weeks to several months.
EXPERT OPINION
Upamostat is an orally bioavailable serine protease inhibitor with an excellent safety profile and favorable pharmacokinetic properties. It has demonstrated preliminary evidence of efficacy against COVID-19, and nonclinical data suggest potential applicability against other viral illnesses, gastrointestinal diseases, and cancer.
Topics: Humans; Serine Proteinase Inhibitors; COVID-19; Antiviral Agents; Gastrointestinal Diseases; Protease Inhibitors
PubMed: 37970658
DOI: 10.1080/13543784.2023.2284385 -
The Lancet. HIV Feb 2022The use of antiretroviral therapy (ART) in pregnancy is important for maternal health, and has been successful in reducing vertical transmission rates to almost zero in... (Review)
Review
The use of antiretroviral therapy (ART) in pregnancy is important for maternal health, and has been successful in reducing vertical transmission rates to almost zero in those taking effective ART regimens with good adherence. However, there are reports of higher rates of low birthweight and preterm births in women with HIV, which can be further exacerbated by ART usage in pregnancy. Protease inhibitors, and ritonavir-boosted lopinavir in particular, might directly contribute to placental and uteroplacental pathology in part by altering plasma concentrations of the essential steroid hormones of pregnancy, progesterone and oestradiol. In this Review, we collate the increasing evidence of dysregulated maternal endocrinology, reproductive physiology, and placental compromise associated with protease inhibitors. Based on findings of placental and decidual effects, we recommend that ritonavir-boosted lopinavir should be avoided in pregnancy, in line with US and European guidelines. Long-term follow-up of children exposed to protease inhibitors in utero is also recommended.
Topics: Anti-HIV Agents; Child; Decidua; Female; HIV Infections; HIV Protease Inhibitors; Humans; Infant, Newborn; Lopinavir; Placenta; Pregnancy; Progesterone; Protease Inhibitors; Ritonavir
PubMed: 34863352
DOI: 10.1016/S2352-3018(21)00249-6