HIV OctaScanner: A Machine Learning Approach to Unveil Proteolytic Cleavage Dynamics in HIV-1 Protease Substrates

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 14, 2025

The rise of resistance to antiretroviral drugs due mutations in human immunodeficiency virus-1 (HIV-1) protease is a major obstacle effective treatment. These alter the drug-binding pocket and reduce drug efficacy by disrupting interactions with inhibitors. Traditional methods, such as biochemical assays structural biology, are crucial for studying enzyme function but time-consuming labor-intensive. To address these challenges, we developed HIV OctaScanner, machine learning algorithm that predicts proteolytic cleavage activity octameric substrates at HIV-1 sites. uses Random Forest (RF) classifier achieves prediction accuracy 89% identification cleavable octamers. This innovative approach facilitates rapid screening potential protease, providing critical insights into guiding development more therapeutic strategies. By improving substrate identification, OctaScanner has support next generation treatments.

Language: Английский

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Evaluation of the Potency of Repurposed Antiretrovirals in HBV Therapy: A Narrative Investigation of the Traditional Medicine Alternatives

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1523 - 1523

Published: Feb. 11, 2025

Hepatitis B is one of the killer communicable diseases, with a global estimation 1.1 million deaths resulting from liver diseases annually. The search for HBV therapeutics has resulted in repurposing existing antiretrovirals (ARVs) treatment, considering their shared common replication mechanisms. This review aimed at evaluating potencies some repurposed ARVs used analyzing mechanisms viral replications and HIV, investigating potentials traditional medicines as an alternative treatment patients. topical keywords drug repurposing, repositioning, antiretrovirals, hepatitis HBV, natural products, medicines, title, abstract were searched PubMed, Web Science, Google Scholar. advanced included five years, 2019-2024. result was filtered 377 to 110 relevant articles. evaluation reveals that CD4+ T cells are targeted by while targets its associated (cirrhosis hepatocellular carcinoma (HCC)). Furthermore, treatments available only prevent or slow down progression cirrhosis, reduce HCC incidence, can improve quality life increase expectancy; however, they not curative HBV. Traditional medicines/natural product extracts phytochemicals exert anti-HBV effects through different improved therapeutic when combined properly. investigation further consideration silico approach might streamline development but also contribute deeper understanding pathogenesis. Therefore, we recommend integration computational design methods medicine screening discovering new bioactive candidates.

Language: Английский

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From Bench to Bedside: Transforming Cancer Therapy with Protease Inhibitors

Targets, Journal Year: 2025, Volume and Issue: 3(1), P. 8 - 8

Published: March 3, 2025

Proteases play a pivotal role in cancer progression, facilitating processes such as extracellular matrix degradation, angiogenesis, and metastasis. Consequently, protease inhibitors have emerged promising therapeutic agents oncology. This review provides comprehensive overview of the mechanisms by which modulate biology, categorizing their target classes, including metalloproteinases, cysteine proteases, serine proteases. We discuss potential both synthetic natural inhibitors, highlighting applications preclinical clinical settings. Furthermore, challenges specificity, toxicity, resistance are addressed, alongside strategies to overcome these limitations through innovative drug designs combination therapies. The future treatment lies precision medicine, leveraging proteomic profiling tailor therapies individual tumors. underscores importance ongoing research development novel approaches harness effectively for management.

Language: Английский

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Research progress on critical viral protease inhibitors for coronaviruses and enteroviruses

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown, P. 130168 - 130168

Published: March 1, 2025

Language: Английский

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Synthesis, screening and validation of cysteine-reactive fragments as chikungunya virus protease inhibitors

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown, P. 130176 - 130176

Published: March 1, 2025

Language: Английский

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Potential Benefits of In Silico Methods: A Promising Alternative in Natural Compound’s Drug Discovery and Repurposing for HBV Therapy

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(3), P. 419 - 419

Published: March 16, 2025

Hepatitis B virus (HBV) is an important global public health issue. The World Health Organization (WHO) 2024 Global Report estimated that the prevalence of people living with HBV infection 254 million, incidence 1.2 million new infections yearly. Previous studies have shown natural compounds antiviral inhibition potentials. In silico methods such as molecular docking, virtual screening, pharmacophore modeling, quantitative structure–activity relationship (QSAR), and dynamic simulations been successfully applied in identifying bioactive strong binding energies treatment targets. COVID-19 pandemic necessitated importance repurposing already approved drugs using methods. This study aimed at unveiling benefits techniques a potential alternative compounds’ drug discovery for therapy. Relevant articles from PubMed, Google Scholar, Web Science were retrieved analyzed. Furthermore, this comprehensively reviewed literature containing identified essential proteins. Notably, hesperidin, quercetin, kaempferol, myricetin, flavonoids hepatitis surface antigen (HBsAg). investigation reveals offer understanding mechanisms action, reveal previously overlooked viral targets (including PreS1 Domain HBsAg cccDNA (Covalently Closed Circular DNA) regulators, facilitate creation specific inhibitors. integration silico, vitro, vivo insights further highlight Moreover, combination compounds, approach, improves chances personalized precision medicine treatment. Therefore, we recommend strategies combine vivo, approaches to effective drugs.

Language: Английский

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Fungi as a Tool to Screen for Microbial Protease Inhibitors

Published: Jan. 1, 2025

Language: Английский

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Structure-based discovery of highly bioavailable, covalent, broad-spectrum coronavirus M ^Pro inhibitors with potent in vivo efficacy

Science Advances, Journal Year: 2025, Volume and Issue: 11(17)

Published: April 23, 2025

The main protease (M Pro ) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a validated drug target. Starting with lead-like dihydrouracil chemotype identified in large-library docking campaign, we improved M inhibition >1000-fold by engaging additional subsites and using latent electrophile to engage Cys 145 . Advanced leads from this series show pan-coronavirus antiviral activity, low clearance mice, for AVI-4773 , rapid reduction viral titers >1,000,000 after just three doses. Both compounds are well distributed mouse tissues, including brain, where concentrations >1000× the 90% effective concentration observed 8 hours oral dosing AVI-4516 shows minimal major cytochrome P450s human proteases. also exhibits synergy RNA-dependent RNA polymerase inhibitor, molnupiravir, cellular infection models. Related analogs strongly inhibit nirmatrelvir-resistant mutant virus. properties differentiated existing clinical preclinical inhibitors will advance therapeutic development against emerging SARS-CoV-2 variants other coronaviruses.

Language: Английский

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Breaking the Chain: Protease Inhibitors as Game Changers in Respiratory Viruses Management

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(15), P. 8105 - 8105

Published: July 25, 2024

Respiratory viral infections (VRTIs) rank among the leading causes of global morbidity and mortality, affecting millions individuals each year across all age groups. These are caused by various pathogens, including rhinoviruses (RVs), adenoviruses (AdVs), coronaviruses (CoVs), which particularly prevalent during colder seasons. Although many VRTIs self-limiting, their frequent recurrence potential for severe health complications highlight critical need effective therapeutic strategies. Viral proteases crucial maturation replication viruses, making them promising targets. This review explores pivotal role in lifecycle respiratory viruses development protease inhibitors as a strategic response to these infections. Recent advances antiviral therapy have highlighted effectiveness curtailing spread severity diseases, especially ongoing COVID-19 pandemic. It also assesses current efforts aimed at identifying developing targeting key from major human RVs, AdVs, (severe acute syndrome coronavirus-2) SARS-CoV-2. Despite recent identification SARS-CoV-2, within last five years, scientific community has devoted considerable time resources investigate existing drugs develop new virus’s main protease. However, research RVs AdVs limited. Therefore, herein, it is proposed utilize this knowledge other tract or dual inhibitors. Finally, detailing mechanisms action potentials inhibitors, aims demonstrate significant transforming management diseases offer insights into future directions.

Language: Английский

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Global Antiviral Peptide Research: A Bibliometric Analysis from 1951 to 2022

Universitas Scientiarum, Journal Year: 2024, Volume and Issue: 29(3), P. 229 - 251

Published: Oct. 10, 2024

Antiviral peptides (AVPs) are small molecules that inhibit the replication of viruses in living cells. AVPs being investigated as potential alternatives to traditional antiviral drugs. The development novel agents is highest concern because some medications can be ineffective and lead resistant emergence. We conducted a bibliometric study on global distribution AVP research comprehend trends patterns field. For this analysis, we retrieved data from Scopus database AVP-related publications 1951 2022, including number publications, citations, authors. Overall, 10,279 papers were published, with an annual average 146 publications. United States released most documents, followed by China, Germany, Kingdom. Since 2001, there has been substantial increase AVPs, prominent themes virology, genetics, protease inhibitors, polypeptide antimicrobial agents, viral entry. This analysis used guide future

Language: Английский

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