Non-nucleoside structured compounds with antiviral activity-past 10 years (2010-2020).
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ABSTRACT:
SUBMITTER: Denel-Bobrowska M
PROVIDER: S-EPMC8769541 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Human immunodeficiency virus (HIV) is the primary infectious agent of acquired immunodeficiency syndrome (AIDS), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the cornerstone of HIV treatment. In the last 20 years, our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs, including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), thio-dihydro-alkoxy-benzyl-oxopyrimidine (S-DABO), diaryltriazine (DATA), diarylpyrimidine (DAPY) analogues, and their hybrid derivatives. Application of integrated modern medicinal strategies, including structure-based drug design, fragment-based optimization, scaffold/fragment hopping, molecular/fragment hybridization, and bioisosterism, led to the development of several highly potent analogues for further evaluations. In this paper, we review the development of NNRTIs in the last two decades using the above optimization strategies, including their structure-activity relationships, molecular modeling, and their binding modes with HIV-1 reverse transcriptase (RT). Future directions and perspectives on the design and associated challenges are also discussed.
| S-EPMC7332669 | biostudies-literature
Project description:We report on the synthesis and characterization of three types of nucleoside tetraphosphate derivatives 4-9 acting as potential prodrugs of d4T nucleotides: (i) the δ-phosph(on)ate is modified by two hydrolytically stable alkyl residues 4 and 5; (ii) the δ-phosph(on)ate is esterified covalently by one biodegradable acyloxybenzyl moiety and a nonbioreversible moiety 6 and 7; or (iii) the δ-phosphate of nucleoside tetraphosphate is masked by two biodegradable prodrug groups 8 and 9. We were able to prove the efficient release of d4T triphosphate (d4TTP, (i)), δ-monoalkylated d4T tetraphosphates (20 and 24, (ii)), and d4T tetraphosphate (d4T4P, (iii)), respectively, by chemical or enzymatic processes. Surprisingly, δ-dialkylated d4T tetraphosphates, δ-monoalkylated d4T tetraphosphates, and d4T4P were substrates for HIV-RT. Remarkably, the antiviral activity of TetraPPPPro-prodrug 7 was improved by 7700-fold (SI 5700) as compared to the parent d4T in CEM/TK- cells, denoting a successful cell membrane passage of these lipophilic prodrugs and an intracellular delivery of the nucleotide metabolites.
| S-EPMC10895676 | biostudies-literature
Project description:Since the first antiviral drug, idoxuridine, was approved in 1963, 90 antiviral drugs categorized into 13 functional groups have been formally approved for the treatment of the following 9 human infectious diseases: (i) HIV infections (protease inhibitors, integrase inhibitors, entry inhibitors, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and acyclic nucleoside phosphonate analogues), (ii) hepatitis B virus (HBV) infections (lamivudine, interferons, nucleoside analogues, and acyclic nucleoside phosphonate analogues), (iii) hepatitis C virus (HCV) infections (ribavirin, interferons, NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors), (iv) herpesvirus infections (5-substituted 2'-deoxyuridine analogues, entry inhibitors, nucleoside analogues, pyrophosphate analogues, and acyclic guanosine analogues), (v) influenza virus infections (ribavirin, matrix 2 protein inhibitors, RNA polymerase inhibitors, and neuraminidase inhibitors), (vi) human cytomegalovirus infections (acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, pyrophosphate analogues, and oligonucleotides), (vii) varicella-zoster virus infections (acyclic guanosine analogues, nucleoside analogues, 5-substituted 2'-deoxyuridine analogues, and antibodies), (viii) respiratory syncytial virus infections (ribavirin and antibodies), and (ix) external anogenital warts caused by human papillomavirus infections (imiquimod, sinecatechins, and podofilox). Here, we present for the first time a comprehensive overview of antiviral drugs approved over the past 50 years, shedding light on the development of effective antiviral treatments against current and emerging infectious diseases worldwide.
| S-EPMC4978613 | biostudies-literature
Project description:Nucleoside analogs require three phosphorylation steps catalyzed by cellular kinases to give their triphosphorylated metabolites. Herein, the synthesis of two types of triphosphate prodrugs of different nucleoside analogs is disclosed. Triphosphates comprising: i) a γ-phosphate or γ-phosphonate bearing a bioreversible acyloxybenzyl group and a long alkyl group and ii) γ-dialkyl phosphate/phosphonate modified nucleoside triphosphate analogs. Almost selective conversion of the former TriPPPro-compounds into the corresponding γ-alkylated nucleoside triphosphate derivatives is demonstrated in CEM/0 cell extracts that proved to be stable toward further hydrolysis. The latter γ-dialkylated triphosphate derivatives lead to the slow formation of the corresponding NDPs. Both types of TriPPPro-compounds are highly potent in wild-type CEM/0 cells and more importantly, they exhibit even better activities against HIV-2 replication in CEM/TK- cell cultures. A finding of major importance is that, in primer extension assays, γ-phosphate-modified-NTPs, γ-mono-alkylated-triphosphates, and NDPs prove to be substrates for HIV-RT but not for cellular DNA-polymerases α,γ.
| S-EPMC10754118 | biostudies-literature
Project description:Tyrosine kinases are implicated in tumorigenesis and progression, and have emerged as major targets for drug discovery. Tyrosine kinase inhibitors (TKIs) inhibit corresponding kinases from phosphorylating tyrosine residues of their substrates and then block the activation of downstream signaling pathways. Over the past 20 years, multiple robust and well-tolerated TKIs with single or multiple targets including EGFR, ALK, ROS1, HER2, NTRK, VEGFR, RET, MET, MEK, FGFR, PDGFR, and KIT have been developed, contributing to the realization of precision cancer medicine based on individual patient's genetic alteration features. TKIs have dramatically improved patients' survival and quality of life, and shifted treatment paradigm of various solid tumors. In this article, we summarized the developing history of TKIs for treatment of solid tumors, aiming to provide up-to-date evidence for clinical decision-making and insight for future studies.
| S-EPMC7590700 | biostudies-literature
Project description:The TIME acronym (tissue, infection/inflammation, moisture balance and edge of wound) was first developed more than 10 years ago, by an international group of wound healing experts, to provide a framework for a structured approach to wound bed preparation; a basis for optimising the management of open chronic wounds healing by secondary intention. However, it should be recognised that the TIME principles are only a part of the systematic and holistic evaluation of each patient at every wound assessment. This review, prepared by the International Wound Infection Institute, examines how new data and evidence generated in the intervening decade affects the original concepts of TIME, and how it is translated into current best practice. Four developments stand out: recognition of the importance of biofilms (and the need for a simple diagnostic), use of negative pressure wound therapy (NPWT), evolution of topical antiseptic therapy as dressings and for wound lavage (notably, silver and polyhexamethylene biguanide) and expanded insight of the role of molecular biological processes in chronic wounds (with emerging diagnostics and theranostics). Tissue: a major advance has been the recognition of the value of repetitive and maintenance debridement and wound cleansing, both in time-honoured and novel methods (notably using NPWT and hydrosurgery). Infection/inflammation: clinical recognition of infection (and non infective causes of persisting inflammation) is critical. The concept of a bacterial continuum through contamination, colonisation and infection is now widely accepted, together with the understanding of biofilm presence. There has been a return to topical antiseptics to control bioburden in wounds, emphasised by the awareness of increasing antibiotic resistance. Moisture: the relevance of excessive or insufficient wound exudate and its molecular components has led to the development and use of a wide range of dressings to regulate moisture balance, and to protect peri-wound skin, and optimise healing. Edge of wound: several treatment modalities are being investigated and introduced to improve epithelial advancement, which can be regarded as the clearest sign of wound healing. The TIME principle remains relevant 10 years on, with continuing important developments that incorporate new evidence for wound care.
| S-EPMC7950760 | biostudies-literature
Project description:In recent years, many studies have focused on the host immune system and its relationship with tumor progression in a variety of solid tumors, including breast cancer. This study investigates recent trends of immunotherapy research in breast cancer and compares the contributions of research from different regions, institutions, and authors. A search of breast cancer and immunotherapy studies that were published between 2010 and 2019-with different keyword combinations-was performed in the Web of Science database. Bibliometric data were collected for analysis. VOSviewer software was used to generate a figure for the keyword's co-occurrence network, so as to implement network visualization analysis. A total of 1,041 publications were identified. The United States and China contributed to approximately 50% of the publications, 336 and 208, respectively. Both countries drove the increase in publications after 2015. A paper entitled "Pembrolizumab in patients with advanced triple-negative breast cancer: Phase IB KEYNOTE-012 Study" that was published in the Journal of Clinical Oncology by Nanda et al. was the most cited (715 citations). The keywords found in this research were grouped into four clusters: "mechanism," "vaccination," "PD-L1," and "chemotherapy." The terms "tumor-infiltrating lymphocytes" and "PD-1/PD-L1" are among the latest hotspots, which mostly appeared in 2017. Author keyword analysis revealed that recent trends in breast cancer immunotherapy focus on the triple-negative breast cancer subtype and PD-1/PD-L1 immune checkpoint pathway and inhibitors. This study analyzed global trends in immunotherapy research on breast cancer over the past 10 years and provided insight into the features and research hotspots of the articles in this issue.
| S-EPMC7661143 | biostudies-literature
Project description:BackgroundPancreatic adenocarcinoma (PDAC) is a lethal cancer with few therapeutic options. Availability of results is a crucial step in interventional research. Our aim was to evaluate results availability for trials in patients with PDAC and explore associated factors.Materials and methodsWe performed a retrospective cohort study and searched the ClinicalTrials.gov registry for trials evaluating PDAC management with a primary completion date between 1 January 2010 and 1 June 2020. Then, we searched for results submitted on ClinicalTrials.gov and/or published. Our primary outcome was the proportion of PDAC trials with available results: submitted on ClinicalTrials.gov (either publicly available or undergoing quality control check) and/or published in a full-text article. The association of predefined trial characteristics with results availability was assessed.ResultsWe identified 551 trials of which 386 (70%) had available results. The cumulative percentage of trials with available results was 21% (95% CI, 18-25%) at 12 months after the primary completion date, 44% (95% CI, 30-48%) at 24 months and 57% (95% CI, 53-61%) at 36 months. Applicable clinical trials, required to comply with the 2007 Food and Drug Administration Amendments Act 801 and its final rule on reporting of results on ClinicalTrials.gov, were more likely to have available results over time (HR 2.1 [95% CI 1.72-2.63], P < .001). Industry-funded, small sample size, and terminated trials were less likely to have available results. Other trial characteristics showed no association with results availability.ConclusionOur results highlight a waste in interventional research studying PDAC.
| S-EPMC9632316 | biostudies-literature
Project description: Not available
| S-BSST893 | biostudies-other
Project description:Occupational exposure to pesticides has been identified as a major trigger of the development of cancer. Pesticides can cause intoxication in the individuals who manipulate them through either inhalation, ingestion, or dermal contact. Given this, we investigated the association between the incidence of cancer and occupational exposure to pesticides through a bibliometric analysis of the studies published between 2011 and 2020, based on 62 papers selected from the Scopus database. The results indicated an exponential increase in the number of studies published over the past decade, with most of the research being conducted in the USA, France, India, and Brazil, although a further 17 nations were also involved in the research on the association between cancer and pesticides. The principal classes of pesticides investigated in relation to their role in intoxication and cancer were insecticides, herbicides, and fungicides. The types of cancer reported most frequently were multiple myeloma, bladder cancer, non-Hodgkin's lymphoma, prostate cancer, leukemia, and breast cancer. Despite the known association between pesticides and cancer, studies are still relatively scarce in comparison with the global scale of the use of these xenobiotic substances, which is related to the increasing demand for agricultural products throughout the world.
| S-EPMC8525621 | biostudies-literature