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  1. Article: Potent SARS-CoV-2 Direct-Acting Antivirals Provide an Important Complement to COVID-19 Vaccines.

    Pelly, Stephen / Liotta, Dennis

    ACS central science

    2021  Volume 7, Issue 3, Page(s) 396–399

    Language English
    Publishing date 2021-03-03
    Publishing country United States
    Document type News
    ISSN 2374-7943
    ISSN 2374-7943
    DOI 10.1021/acscentsci.1c00258
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Potent SARS-CoV‑2 Direct-Acting Antivirals Provide an Important Complement to COVID-19 Vaccines

    Stephen Pelly / Dennis Liotta

    ACS Central Science, Vol 7, Iss 3, Pp 396-

    2021  Volume 399

    Keywords Chemistry ; QD1-999
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher American Chemical Society
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Synthesis and biological evaluation of 5'-C-methyl nucleotide prodrugs for treating HCV infections.

    Dasari, Madhuri / Ma, Peipei / Pelly, Stephen C / Sharma, Savita K / Liotta, Dennis C

    Bioorganic & medicinal chemistry letters

    2020  Volume 30, Issue 23, Page(s) 127539

    Abstract: Nucleotide prodrugs are of great clinical interest for treating a variety of viral infections due to their ability to target tissues selectively and to deliver relatively high concentrations of the active nucleotide metabolite intracellularly. However, ... ...

    Abstract Nucleotide prodrugs are of great clinical interest for treating a variety of viral infections due to their ability to target tissues selectively and to deliver relatively high concentrations of the active nucleotide metabolite intracellularly. However, their clinical successes have been limited, oftentimes due to unwanted in vivo metabolic processes that reduce the quantities of nucleoside triphosphate that reach the site of action. In an attempt to circumvent this, we designed novel nucleosides that incorporate a sterically bulky group at the 5'-carbon of the phosphoester prodrug, which we reasoned would reduce the amounts of non-productive PO bond cleavage back to the corresponding nucleoside by nucleotidases. Molecular docking studies with the NS5B HCV polymerase suggested that a nucleotide containing a 5'-methyl group could be accommodated. Therefore, we synthesized mono- and diphosphate prodrugs of 2',5'-C-dimethyluridine stereoselectively and evaluated their cytotoxicity and anti-HCV activity in the HCV replicon assay. All four prodrugs exhibited anti-HCV activity with IC
    MeSH term(s) Antiviral Agents/chemical synthesis ; Antiviral Agents/metabolism ; Antiviral Agents/pharmacology ; Cell Line ; Cytomegalovirus/drug effects ; Humans ; Microbial Sensitivity Tests ; Molecular Docking Simulation ; Prodrugs/chemical synthesis ; Prodrugs/metabolism ; Prodrugs/pharmacology ; Protein Binding ; Uracil Nucleotides/chemical synthesis ; Uracil Nucleotides/metabolism ; Uracil Nucleotides/pharmacology ; Viral Nonstructural Proteins/metabolism
    Chemical Substances Antiviral Agents ; Prodrugs ; Uracil Nucleotides ; Viral Nonstructural Proteins ; NS-5 protein, hepatitis C virus (EC 2.7.7.48)
    Language English
    Publishing date 2020-09-09
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2020.127539
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3203: Show issues Location:
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  4. Article ; Online: Discovery of 5'-Substituted 5-Fluoro-2'-deoxyuridine Monophosphate Analogs: A Novel Class of Thymidylate Synthase Inhibitors.

    Dasari, Madhuri / Pelly, Stephen C / Geng, Jiafeng / Gold, Hannah B / Pribut, Nicole / Sharma, Savita K / D'Erasmo, Michael P / Bartsch, Perry W / Sun, Carrie / Toti, Kiran / Arnold, Rebecca S / Petros, John A / Xu, Lingjie / Jiang, Yi / Miller, Eric J / Liotta, Dennis C

    ACS pharmacology & translational science

    2023  Volume 6, Issue 5, Page(s) 702–709

    Abstract: 5-Fluorouracil and 5-fluorouracil-based prodrugs have been used clinically for decades to treat cancer. Their anticancer effects are most prominently ascribed to inhibition of thymidylate synthase (TS) by metabolite 5-fluoro-2'-deoxyuridine 5'- ... ...

    Abstract 5-Fluorouracil and 5-fluorouracil-based prodrugs have been used clinically for decades to treat cancer. Their anticancer effects are most prominently ascribed to inhibition of thymidylate synthase (TS) by metabolite 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). However, 5-fluorouracil and FdUMP are subject to numerous unfavorable metabolic events that can drive undesired systemic toxicity. Our previous research on antiviral nucleotides suggested that substitution at the nucleoside 5'-carbon imposes conformational restrictions on the corresponding nucleoside monophosphates, rendering them poor substrates for productive intracellular conversion to viral polymerase-inhibiting triphosphate metabolites. Accordingly, we hypothesized that 5'-substituted analogs of FdUMP, which is uniquely active at the monophosphate stage, would inhibit TS while preventing undesirable metabolism. Free energy perturbation-derived relative binding energy calculations suggested that 5'(
    Language English
    Publishing date 2023-02-23
    Publishing country United States
    Document type Journal Article
    ISSN 2575-9108
    ISSN (online) 2575-9108
    DOI 10.1021/acsptsci.2c00252
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: The Negative Allosteric Modulator EU1794-4 Reduces Single-Channel Conductance and Ca

    Perszyk, Riley E / Zheng, Zhaoshi / Banke, Tue G / Zhang, Jing / Xie, Lingling / McDaniel, Miranda J / Katzman, Brooke M / Pelly, Stephen C / Yuan, Hongjie / Liotta, Dennis C / Traynelis, Stephen F

    Molecular pharmacology

    2021  Volume 99, Issue 5, Page(s) 399–411

    Abstract: NMDA receptors are ligand-gated ion channels that mediate a slow, ... ...

    Abstract NMDA receptors are ligand-gated ion channels that mediate a slow, Ca
    MeSH term(s) Allosteric Regulation/drug effects ; Animals ; Brain/drug effects ; Brain/metabolism ; Calcium/metabolism ; Glutamic Acid/metabolism ; Glycine/metabolism ; HEK293 Cells ; Humans ; Permeability/drug effects ; Receptors, N-Methyl-D-Aspartate/metabolism ; Xenopus laevis
    Chemical Substances Receptors, N-Methyl-D-Aspartate ; Glutamic Acid (3KX376GY7L) ; Calcium (SY7Q814VUP) ; Glycine (TE7660XO1C) ; N-methyl D-aspartate receptor subtype 2A (VH92ICR8HX)
    Language English
    Publishing date 2021-03-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 124034-1
    ISSN 1521-0111 ; 0026-895X
    ISSN (online) 1521-0111
    ISSN 0026-895X
    DOI 10.1124/molpharm.120.000218
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 525: Show issues Location:
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  6. Article: Aryl Substituted Benzimidazolones as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors.

    Pribut, Nicole / Basson, Adriaan E / van Otterlo, Willem A L / Liotta, Dennis C / Pelly, Stephen C

    ACS medicinal chemistry letters

    2019  Volume 10, Issue 2, Page(s) 196–202

    Abstract: Since the discovery of HIV as the etiological agent of AIDS, the virus has infected millions of people each year. Fortunately, with the use of HAART, viremia can be suppressed to below detectable levels in the infected individuals, which significantly ... ...

    Abstract Since the discovery of HIV as the etiological agent of AIDS, the virus has infected millions of people each year. Fortunately, with the use of HAART, viremia can be suppressed to below detectable levels in the infected individuals, which significantly improves their quality of life and prevents the onset of AIDS. However, HAART is not curative and issues relating to adherence and drug resistance may lead to the re-emergence of viremia, the development of AIDS, and ultimately death. To address a pressing need for the development of new and efficacious antiretroviral agents with activity against viruses bearing prevalent resistant mutations, we have designed two generations of benzimidazolone derivatives as HIV non-nucleoside reverse transcriptase inhibitors. The first generation benzimidazolone inhibitors were found to be potent inhibitors of wild-type HIV reverse transcriptase but were ineffective in the presence of common resistance mutations such as K103N and Y181C. A second generation benzimidazolone inhibitor (compound 42) not only showed inhibitory activity against wild-type HIV but also remained active against HIV containing the K103N, Y181C, and K103N/Y181C drug resistance mutations.
    Language English
    Publishing date 2019-01-17
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.8b00549
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  7. Article ; Online: Covalent Allosteric Inhibitors of Akt Generated Using a Click Fragment Approach.

    van der Westhuizen, Leandi / Weisner, Jörn / Taher, Abu / Landel, Ina / Quambusch, Lena / Lindemann, Marius / Uhlenbrock, Niklas / Müller, Matthias P / Green, Ivan R / Pelly, Stephen C / Rauh, Daniel / van Otterlo, Willem A L

    ChemMedChem

    2022  Volume 17, Issue 10, Page(s) e202100776

    Abstract: Akt is a protein kinase that has been implicated in the progression of cancerous tumours. A number of covalent allosteric Akt inhibitors are known, and based on these scaffolds, a small library of novel potential covalent allosteric imidazopyridine-based ...

    Abstract Akt is a protein kinase that has been implicated in the progression of cancerous tumours. A number of covalent allosteric Akt inhibitors are known, and based on these scaffolds, a small library of novel potential covalent allosteric imidazopyridine-based inhibitors was designed. The envisaged compounds were synthesised, with click chemistry enabling a modular approach to a number of the target compounds. The binding modes, potencies and antiproliferative activities of these synthesised compounds were explored, thereby furthering the structure activity relationship knowledge of this class of Akt inhibitors. Three novel covalent inhibitors were identified, exhibiting moderate activity against Akt1 and various cancer cell lines, potentially paving the way for future covalent allosteric inhibitors with improved properties.
    MeSH term(s) Allosteric Regulation ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Structure-Activity Relationship
    Chemical Substances Protein Kinase Inhibitors ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
    Language English
    Publishing date 2022-03-09
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2218496-X
    ISSN 1860-7187 ; 1860-7179
    ISSN (online) 1860-7187
    ISSN 1860-7179
    DOI 10.1002/cmdc.202100776
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    Zs.A 6280: Show issues Location:
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  8. Article: Design and Optimization of Novel Competitive, Non-peptidic, SARS-CoV-2 M

    Jacobs, Leon / van der Westhuyzen, Aletta / Pribut, Nicole / Dentmon, Zackery W / Cui, Dan / D'Erasmo, Michael P / Bartsch, Perry W / Liu, Ken / Cox, Robert M / Greenlund, Sujay F / Plemper, Richard K / Mitchell, Deborah / Marlow, Joshua / Andrews, Meghan K / Krueger, Rebecca E / Sticher, Zachary M / Kolykhalov, Alexander A / Natchus, Michael G / Zhou, Bin /
    Pelly, Stephen C / Liotta, Dennis C

    ACS medicinal chemistry letters

    2023  Volume 14, Issue 10, Page(s) 1434–1440

    Abstract: The SARS-CoV-2 main protease ( ... ...

    Abstract The SARS-CoV-2 main protease (M
    Language English
    Publishing date 2023-09-28
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.3c00335
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  9. Article ; Online: Synthesis of five libraries of 6,5-fused heterocycles to establish the importance of the heterocyclic core for antiplasmodial activity.

    Jacobs, Leon / de Kock, Carmen / Taylor, Dale / Pelly, Stephen C / Blackie, Margaret A L

    Bioorganic & medicinal chemistry

    2018  Volume 26, Issue 21, Page(s) 5730–5741

    Abstract: Research has indicated that N-myristoyl transferase, an enzyme that catalyzes the addition of a myristate group to the N-terminal glycine residues of proteins, is involved in the myristoylation of more than 100 proteins. Genetic knockdown of the enzyme ... ...

    Abstract Research has indicated that N-myristoyl transferase, an enzyme that catalyzes the addition of a myristate group to the N-terminal glycine residues of proteins, is involved in the myristoylation of more than 100 proteins. Genetic knockdown of the enzyme proved detrimental for the viability of the parasite P. knowlesi. A crystal structure of P. vivax N-myristoyl transferase (pvNMT), containing a 3-methyl benzofuran ligand has made it possible to assess key amino acid residue-ligand interactions. We synthesized five libraries of 6,5-fused heterocycles to establish the importance of the heterocycles as core scaffolds, as well as introduced various aromatic amides and esters to determine which carbonylic group affects the potency of each heterocyclic antiplasmodial agent.
    MeSH term(s) Antimalarials/chemical synthesis ; Antimalarials/chemistry ; Antimalarials/pharmacology ; Benzimidazoles/chemical synthesis ; Benzimidazoles/chemistry ; Benzimidazoles/pharmacology ; Benzoxazoles/chemical synthesis ; Benzoxazoles/chemistry ; Benzoxazoles/pharmacology ; Indoles/chemical synthesis ; Indoles/chemistry ; Indoles/pharmacology ; Molecular Structure ; Plasmodium falciparum/drug effects ; Small Molecule Libraries/chemical synthesis ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Structure-Activity Relationship ; Thiophenes/chemical synthesis ; Thiophenes/chemistry ; Thiophenes/pharmacology
    Chemical Substances Antimalarials ; Benzimidazoles ; Benzoxazoles ; Indoles ; Small Molecule Libraries ; Thiophenes
    Language English
    Publishing date 2018-10-27
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1161284-8
    ISSN 1464-3391 ; 0968-0896
    ISSN (online) 1464-3391
    ISSN 0968-0896
    DOI 10.1016/j.bmc.2018.10.029
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    Zs.A 3815: Show issues Location:
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  10. Article ; Online: A Machine Learning Approach for Predicting HIV Reverse Transcriptase Mutation Susceptibility of Biologically Active Compounds.

    Kaiser, Thomas M / Burger, Pieter B / Butch, Christopher J / Pelly, Stephen C / Liotta, Dennis C

    Journal of chemical information and modeling

    2018  Volume 58, Issue 8, Page(s) 1544–1552

    Abstract: HIV resistance emerging against antiretroviral drugs represents a great threat to the continued prolongation of the lifespans of HIV-infected patients. Therefore, methods capable of predicting resistance susceptibility in the development of compounds are ...

    Abstract HIV resistance emerging against antiretroviral drugs represents a great threat to the continued prolongation of the lifespans of HIV-infected patients. Therefore, methods capable of predicting resistance susceptibility in the development of compounds are in great need. By targeting the major reverse transcription residues Y181, K103, and L100, we used the biological activities of compounds against these enzymes and the wild-type reverse transcriptase to create Naïve Bayes Networks. Through this machine learning approach, we could predict, with high accuracy, whether a compound would be susceptible to a loss of potency due to resistance. Also, we could perfectly predict retrospectively whether compounds would be susceptible to both a K103 mutant RT and a Y181 mutant RT. In the study presented here, our method outperformed a traditional molecular mechanics approach. This method should be of broad interest beyond drug discovery efforts, and serves to expand the utility of machine learning for the prediction of physical, chemical, or biological properties using the vast information available in the literature.
    MeSH term(s) Bayes Theorem ; Drug Discovery/methods ; Drug Resistance, Viral ; HIV Infections/drug therapy ; HIV Reverse Transcriptase/genetics ; HIV Reverse Transcriptase/metabolism ; HIV-1/drug effects ; HIV-1/enzymology ; Humans ; Machine Learning ; Models, Biological ; Point Mutation ; Reverse Transcriptase Inhibitors/chemistry ; Reverse Transcriptase Inhibitors/pharmacology
    Chemical Substances Reverse Transcriptase Inhibitors ; HIV Reverse Transcriptase (EC 2.7.7.49)
    Language English
    Publishing date 2018-07-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 190019-5
    ISSN 1549-960X ; 0095-2338
    ISSN (online) 1549-960X
    ISSN 0095-2338
    DOI 10.1021/acs.jcim.7b00475
    Database MEDical Literature Analysis and Retrieval System OnLINE

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