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Biochemical and Biophysical Research... May 2022Flavivirus, such as Dengue Virus (DENV) and Zika virus (ZIKV), infects millions of people and cause the death of thousands of people every year. Despite many efforts,...
Flavivirus, such as Dengue Virus (DENV) and Zika virus (ZIKV), infects millions of people and cause the death of thousands of people every year. Despite many efforts, there is no approved anti-flaviviral treatment available. In particular, some antiflavivirus compounds were investigated the cellular activities of DENV and ZIKV, but lacking the exploration of specific target enzyme, thereby resulting in the hindrance of structure-based drug design. One example is Montlukast, which was found to inhibit the replicon replication in DENV and ZIKV infected cells, with EC values as 1.03 μM (DENV) and 1.14 μM (ZIKV), while the underlying mechanism remains unclear. In our study, the inhibitory mechanisms of Montelukast against the replicon replication of DENV and ZIKV infected cells were studied by using in silico approaches including inverse virtual screening (IVS), molecular dynamics (MD) simulations and binding free energy calculation, and validated through in vitro protease assay, confirming Montelukast could bind to NS2B-NS3 proteases of DENV and ZIKV as a competitive inhibitor (IC for DENV: 25.65 μM, for ZIKV: 15.57 μM). Moreover, Montelukast has no potential off-target effect on NS2B-NS3 protease from thrombin and trypsin inhibitory assay. Overall, Montelukast may be used as a potential candidate to block NS2B-NS3 protease as well as lead for structural modification.
Topics: Acetates; Antiviral Agents; Cyclopropanes; Enzyme Inhibitors; Flavivirus; Humans; Peptide Hydrolases; Protease Inhibitors; Quinolines; Sulfides; Viral Nonstructural Proteins; Zika Virus; Zika Virus Infection
PubMed: 35339757
DOI: 10.1016/j.bbrc.2022.03.064 -
International Journal of Antimicrobial... Jul 2023Data indicate that certain combination antiretroviral treatment (cART) regimens, particularly protease inhibitor (PI)-based regimens, and cART initiation before... (Meta-Analysis)
Meta-Analysis Review
Maternal antiretroviral treatment for HIV infection and risk of small-for-gestational-age birth: A systematic review and meta-analysis of protease inhibitor-based treatment and timing of treatment.
BACKGROUND
Data indicate that certain combination antiretroviral treatment (cART) regimens, particularly protease inhibitor (PI)-based regimens, and cART initiation before conception may be associated with adverse pregnancy outcomes. The risk of having a small-for-gestational-age (SGA) infant was examined among pregnant HIV-infected mothers on 1) PI-based compared to non-PI-based cART, and 2) any cART initiated before compared to after conception.
METHODS
A search was conducted using PubMed, Embase, and the Cochrane Library, and a systematic review was performed of studies published since Dec 1, 1995. Effect estimates with 95% confidence intervals (CIs) were extracted and meta-analyses with random-effects models were conducted. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation tool.
FINDINGS
Of 783 identified studies, 28 fulfilled the inclusion criteria. Meta-analysis indicated that PI-based cART was associated with a possible slightly increased risk of SGA compared with non-PI-based cART (pooled odds ratio [OR]: 1·09; CI: 0·76, 1·55). Initiation of cART before conception was also associated with a possible slightly increased risk of SGA compared with after conception (pooled OR: 1·08; CI: 0·95, 1·22). The overall certainty of evidence was very low and low for the first and second research questions, respectively.
INTERPRETATION
Although the benefits of cART largely outweigh the risks, these findings indicate the possibility of slightly increased risks of having an SGA infant. This indicates that careful monitoring of fetuses exposed to PI-based cART or cART before pregnancy might be reasonable. Based on the uncertainty of evidence, further research may change this conclusion.
Topics: Pregnancy; Infant; Female; Humans; HIV Infections; Anti-HIV Agents; Pregnancy Outcome; Protease Inhibitors
PubMed: 37121443
DOI: 10.1016/j.ijantimicag.2023.106823 -
European Journal of Medicinal Chemistry Dec 2021Cathepsin C, an important lysosomal cysteine protease, mediates the maturation process of neutrophil serine proteases, and participates in the inflammation and immune... (Review)
Review
Cathepsin C, an important lysosomal cysteine protease, mediates the maturation process of neutrophil serine proteases, and participates in the inflammation and immune regulation process associated with polymorphonuclear neutrophils. Therefore, cathepsin C is considered to be an attractive target for treating inflammatory diseases. With INS1007 (trade name: brensocatib) being granted a breakthrough drug designation by FDA for the treatment of Adult Non-cystic Fibrosis Bronchiectasis and Coronavirus Disease 2019, the development of cathepsin C inhibitor will attract attentions from medicinal chemists in the future soon. Here, we summarized the research results of cathepsin C as a therapeutic target, focusing on the development of cathepsin C inhibitor, and provided guidance and reference opinions for the upcoming development boom of cathepsin C inhibitor.
Topics: Anti-Inflammatory Agents; COVID-19; Cathepsin C; Drug Discovery; Humans; Papillon-Lefevre Disease; Protease Inhibitors; Pulmonary Disease, Chronic Obstructive; SARS-CoV-2; Serine Endopeptidases; COVID-19 Drug Treatment
PubMed: 34492551
DOI: 10.1016/j.ejmech.2021.113818 -
Biomacromolecules Jun 2022The derivative of protease inhibitor ritonavir (5-methyl-4-oxohexanoic acid ritonavir ester; RD) was recently recognized as a potent P-gp inhibitor and cancerostatic...
Simultaneous Delivery of Doxorubicin and Protease Inhibitor Derivative to Solid Tumors via Star-Shaped Polymer Nanomedicines Overcomes P-gp- and STAT3-Mediated Chemoresistance.
The derivative of protease inhibitor ritonavir (5-methyl-4-oxohexanoic acid ritonavir ester; RD) was recently recognized as a potent P-gp inhibitor and cancerostatic drug inhibiting the proteasome and STAT3 signaling. Therefore, we designed high-molecular-weight HPMA copolymer conjugates with a PAMAM dendrimer core bearing both doxorubicin (Dox) and RD (Star-RD + Dox) to increase the circulation half-life to maximize simultaneous delivery of Dox and RD into the tumor. Star-RD inhibited P-gp activity, potently sensitizing both low- and high-P-gp-expressing cancer cells to the cytostatic and proapoptotic activity of Dox in vitro. Star-RD + Dox possessed higher cytostatic and proapoptotic activities compared to Star-Dox and the equivalent mixture of Star-Dox and Star-RD in vitro. Star-RD + Dox efficiently inhibited STAT3 signaling and induced caspase-3 activation and DNA fragmentation in cancer cells in vivo. Importantly, Star-RD + Dox was found to have superior antitumor activity in terms of tumor growth inhibition and increased survival of mice bearing P-gp-expressing tumors.
Topics: Animals; Cytostatic Agents; Doxorubicin; Drug Resistance, Neoplasm; Mice; Nanomedicine; Neoplasms; Polymers; Protease Inhibitors; Ritonavir
PubMed: 35584053
DOI: 10.1021/acs.biomac.2c00256 -
Methods in Molecular Biology (Clifton,... 2024Protease inhibitors of the alpha-macroglobulin family (αM) have a unique mechanism that allows them to trap proteases that is dependent not on the protease's class, but...
Protease inhibitors of the alpha-macroglobulin family (αM) have a unique mechanism that allows them to trap proteases that is dependent not on the protease's class, but rather on its cleavage specificity. Proteases trigger a conformational change in the αM protein by cleaving within a "bait region," resulting in the sequestering of the protease inside the αM molecule. This nonspecific inhibitory mechanism appears to have arisen early in the αM family, and the broad protease-trapping capacity that it allows may play a role in pathogen defense.Human α-macroglobulin (A2M) is a tetrameric αM whose bait region is permissive to cleavage by most proteases, making it a broad-spectrum protease inhibitor. Recent work has demonstrated that the inhibitory capacity of A2M derives directly from its bait region sequence: modifying the bait region sequence to introduce or remove protease cleavage sites will modify A2M's inhibition of the relevant proteases accordingly. Thus, changing the amino acid sequence of the bait region presents an effective avenue for protein engineering of new protease inhibitors if the substrate specificity of the target protease is known. The design of new A2M-based protease inhibitors with tailored inhibitory capacities has potential applications in basic research and the clinic. In this chapter, we describe the general approach and considerations for the bait region engineering of A2M.
Topics: Humans; Pregnancy; Female; Pregnancy-Associated alpha 2-Macroglobulins; Protease Inhibitors; Enzyme Inhibitors; alpha-Macroglobulins; Endopeptidases; Peptide Hydrolases; Macroglobulins
PubMed: 38038947
DOI: 10.1007/978-1-0716-3589-6_21 -
Biomolecules Jul 2022Protease inhibitors are widely studied since the unrestricted activity of proteases can cause extensive organ lesions. In particular, elastase activity is involved in...
Protease inhibitors are widely studied since the unrestricted activity of proteases can cause extensive organ lesions. In particular, elastase activity is involved in the pathophysiology of acute lung injury, for example during SARS-CoV-2 infection, while serine proteases and thrombin-like proteases are involved in the development and/or pathology of the nervous system. Natural protease inhibitors have the advantage to be reversible and with few side effects and thus are increasingly considered as new drugs. Kunitz-type protease inhibitors (KTPIs), reported in the venom of various organisms, such as wasps, spiders, scorpions, and snakes, have been studied for their potent anticoagulant activity and widespread protease inhibitor activity. Putative KTPI anticoagulants have been identified in transcriptomic resources obtained for two blister beetle species, and . The KTPIs of and were characterized by combined transcriptomic and bioinformatics methodologies. The full-length mRNA sequences were divided on the base of the sequence of the active sites of the putative proteins. In silico protein structure analyses of each group of translational products show the biochemical features of the active sites and the potential protease targets. Validation of these genes is the first step for considering these molecules as new drugs for use in medicine.
Topics: Animals; COVID-19; Coleoptera; Protease Inhibitors; SARS-CoV-2; Serine Proteases
PubMed: 35883544
DOI: 10.3390/biom12070988 -
European Journal of Trauma and... Jun 2022Trauma and hemorrhagic shock (T/HS) is a major cause of morbidity and mortality. Existing treatment options are largely limited to source control and fluid and blood...
PURPOSE
Trauma and hemorrhagic shock (T/HS) is a major cause of morbidity and mortality. Existing treatment options are largely limited to source control and fluid and blood repletion. Previously, we have shown that enteral protease inhibition improves outcomes in experimental models of T/HS by protecting the gut from malperfusion and ischemia. However, enteral protease inhibition was achieved invasively, by laparotomy and direct injection of tranexamic acid (TXA) into the small intestine. In this study, we tested a minimally invasive method of enteral protease inhibitor infusion in experimental T/HS that can be readily adapted for clinical use.
METHODS
Wistar rats were exsanguinated to a mean arterial blood pressure (MABP) of 40 mmHg, with laparotomy to induce trauma. Hypovolemia was maintained for 120 min and was followed by reperfusion of shed blood. Animals were monitored for an additional 120 min. A modified orogastric multi-lumen tube was developed to enable rapid enteral infusion of a protease inhibitor solution while simultaneously mitigating risk of reflux aspiration into the airways. The catheter was used to deliver TXA (T/HS + TXA) or vehicle (T/HS) continuously into the proximal small intestine, starting 20 min into the ischemic period.
RESULTS
Rats treated with enteral protease inhibition (T/HS + TXA) displayed improved outcomes compared to control animals (T/HS), including significantly improved MABP (p = 0.022) and lactate (p = 0.044). Mass spectrometry-based analysis of the plasma peptidome after T/HS indicated mitigation of systemic proteolysis in T/HS + TXA.
CONCLUSION
Minimally invasive, continuous enteral protease inhibitor delivery improves outcomes in T/HS and is readily translatable to the clinical arena.
Topics: Animals; Disease Models, Animal; Humans; Intestine, Small; Ischemia; Protease Inhibitors; Rats; Rats, Wistar; Shock, Hemorrhagic; Tranexamic Acid
PubMed: 33483765
DOI: 10.1007/s00068-020-01591-y -
Pesticide Biochemistry and Physiology Oct 2022Pest management is challenged with resistant herbivores and problems regarding human health and environmental issues. Indeed, the greatest challenge to modern...
Bovine pancreatic trypsin inhibitor and soybean Kunitz trypsin inhibitor: Differential effects on proteases and larval development of the soybean pest Anticarsia gemmatalis (Lepidoptera: Noctuidae).
Pest management is challenged with resistant herbivores and problems regarding human health and environmental issues. Indeed, the greatest challenge to modern agriculture is to protect crops from pests and still maintain environmental quality. This study aimed to analyze by in silico, in vitro, and in vivo approaches to the feasibility of using the inhibitory protein extracted from mammals - Bovine Pancreatic Trypsin Inhibitor (BPTI) as a potential inhibitor of digestive trypsins from the pest Anticarsia gemmatalis and comparing the results with the host-plant inhibitor - Soybean Kunitz Trypsin Inhibitor (SKTI). BPTI and SKTI interacts with A. gemmatalis trypsin-like enzyme competitively, through hydrogen and hydrophobic bonds. A. gemmatalis larvae exposed to BPTI did not show two common adaptative mechanisms i.e., proteolytic degradation and overproduction of proteases, presenting highly reduced trypsin-like activity. On the other hand, SKTI-fed larvae did not show reduced trypsin-like activity, presenting overproduction of proteases and SKTI digestion. In addition, the larval survival was reduced by BPTI similarly to SKTI, and additionally caused a decrease in pupal weight. The non-plant protease inhibitor BPTI presents intriguing element to compose biopesticide formulations to help decrease the use of conventional refractory pesticides into integrated pest management programs.
Topics: Animals; Aprotinin; Biological Control Agents; Cattle; Hydrogen; Larva; Moths; Peptide Hydrolases; Pesticides; Protease Inhibitors; Glycine max; Trypsin; Trypsin Inhibitors
PubMed: 36127063
DOI: 10.1016/j.pestbp.2022.105188 -
International Journal of Molecular... Dec 2021Since December 2019, the new SARS-CoV-2-related COVID-19 disease has caused a global pandemic and shut down the public life worldwide. Several proteins have emerged as... (Review)
Review
Since December 2019, the new SARS-CoV-2-related COVID-19 disease has caused a global pandemic and shut down the public life worldwide. Several proteins have emerged as potential therapeutic targets for drug development, and we sought out to review the commercially available and marketed SARS-CoV-2-targeted libraries ready for high-throughput virtual screening (HTVS). We evaluated the SARS-CoV-2-targeted, protease-inhibitor-focused and protein-protein-interaction-inhibitor-focused libraries to gain a better understanding of how these libraries were designed. The most common were ligand- and structure-based approaches, along with various filtering steps, using molecular descriptors. Often, these methods were combined to obtain the final library. We recognized the abundance of targeted libraries offered and complimented by the inclusion of analytical data; however, serious concerns had to be raised. Namely, vendors lack the information on the library design and the references to the primary literature. Few references to active compounds were also provided when using the ligand-based design and usually only protein classes or a general panel of targets were listed, along with a general reference to the methods, such as molecular docking for the structure-based design. No receptor data, docking protocols or even references to the applied molecular docking software (or other HTVS software), and no pharmacophore or filter design details were given. No detailed functional group or chemical space analyses were reported, and no specific orientation of the libraries toward the design of covalent or noncovalent inhibitors could be observed. All libraries contained pan-assay interference compounds (PAINS), rapid elimination of swill compounds (REOS) and aggregators, as well as focused on the drug-like model, with the majority of compounds possessing their molecular mass around 500 g/mol. These facts do not bode well for the use of the reviewed libraries in drug design and lend themselves to commercial drug companies to focus on and improve.
Topics: Antiviral Agents; Databases, Chemical; Drug Design; High-Throughput Screening Assays; Humans; Molecular Docking Simulation; Protease Inhibitors; Protein Interaction Domains and Motifs; SARS-CoV-2; Small Molecule Libraries
PubMed: 35008818
DOI: 10.3390/ijms23010393 -
Current HIV Research 2023Viruses belong to the class of micro-organisms that are well known for causing infections in the human body. Antiviral medications are given out to prevent the spread of... (Review)
Review
Viruses belong to the class of micro-organisms that are well known for causing infections in the human body. Antiviral medications are given out to prevent the spread of disease-causing viruses. When the viruses are actively reproducing, these agents have their greatest impact. It is particularly challenging to develop virus-specific medications since viruses share the majority of the metabolic functions of the host cell. In the continuous search for better antiviral agents, the United States Food and Drug Administration (USFDA) approved a new drug named Evotaz on January 29, 2015 for the treatment of human immunodeficiency virus (HIV). Evotaz is a combined once-daily fixed drug, containing Atazanavir, an HIV protease inhibitor, and cobicistat, an inhibitor of the human liver cytochrome P450 (CYP) enzyme. The medication is created such that it can kill viruses by concurrently inhibiting protease and CYP enzymes. The medicine is still being studied for a number of criteria, but its usefulness in children under the age of 12 is currently unknown. The preclinical and clinical characteristics of Evotaz, as well as its safety and efficacy profiles and a comparison of the novel drug with antiviral medications presently available in the market, are the main topics of this review paper.
Topics: Child; Humans; Anti-HIV Agents; Anti-Infective Agents; Antiviral Agents; Atazanavir Sulfate; Cobicistat; Cytochrome P-450 Enzyme System; Drug Interactions; HIV Infections; HIV Protease Inhibitors; HIV-1; Protease Inhibitors; United States
PubMed: 37221692
DOI: 10.2174/1570162X21666230522123631