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  1. Article ; Online: Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic.

    Shurtleff, Valerie W / Layton, Mark E / Parish, Craig A / Perkins, James J / Schreier, John D / Wang, Yunyi / Adam, Gregory C / Alvarez, Nadine / Bahmanjah, Soheila / Bahnck-Teets, Carolyn M / Boyce, Christopher W / Burlein, Christine / Cabalu, Tamara D / Campbell, Brian T / Carroll, Steven S / Chang, Wonsuk / de Lera Ruiz, Manuel / Dolgov, Enriko / Fay, John F /
    Fox, Nicholas G / Goh, Shih Lin / Hartingh, Timothy J / Hurzy, Danielle M / Kelly, Michael J / Klein, Daniel J / Klingler, Franca-Maria / Krishnamurthy, Harini / Kudalkar, Shalley / Mayhood, Todd W / McKenna, Philip M / Murray, Edward M / Nahas, Debbie / Nawrat, Christopher C / Park, Steven / Qian, Dongming / Roecker, Anthony J / Sharma, Vijeta / Shipe, William D / Su, Jing / Taggart, Robert V / Truong, Quang / Wu, Yin / Zhou, Xiaoyan / Zhuang, Ningning / Perlin, David S / Olsen, David B / Howe, John A / McCauley, John A

    Journal of medicinal chemistry

    2024  Volume 67, Issue 5, Page(s) 3935–3958

    Abstract: As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the ... ...

    Abstract As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.
    MeSH term(s) Humans ; Glutamine/chemistry ; SARS-CoV-2 ; Cysteine Endopeptidases/chemistry ; COVID-19 ; Inventions ; Protease Inhibitors/pharmacology ; Amides ; Antiviral Agents/pharmacology ; Antiviral Agents/chemistry
    Chemical Substances Glutamine (0RH81L854J) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Protease Inhibitors ; Amides ; Antiviral Agents
    Language English
    Publishing date 2024-02-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.3c02248
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Cerastecins inhibit membrane lipooligosaccharide transport in drug-resistant Acinetobacter baumannii.

    Wang, Hao / Ishchenko, Andrii / Skudlarek, Jason / Shen, Pamela / Dzhekieva, Liudmila / Painter, Ronald E / Chen, Yun-Ting / Bukhtiyarova, Marina / Leithead, Andrew / Tracy, Rodger / Babaoglu, Kerim / Bahnck-Teets, Carolyn / Buevich, Alexei / Cabalu, Tamara D / Labroli, Marc / Lange, Henry / Lei, Ying / Li, Wei / Liu, Jian /
    Mann, Paul A / Meng, Tao / Mitchell, Helen J / Mulhearn, James / Scapin, Giovanna / Sha, Deyou / Shaw, Anthony W / Si, Qian / Tong, Ling / Wu, Chengwei / Wu, Zhe / Xiao, Jing Chen / Xu, Min / Zhang, Li-Kang / McKenney, David / Miller, Randy R / Black, Todd A / Cooke, Andrew / Balibar, Carl J / Klein, Daniel J / Raheem, Izzat / Walker, Scott S

    Nature microbiology

    2024  Volume 9, Issue 5, Page(s) 1244–1255

    Abstract: Carbapenem-resistant Acinetobacter baumannii infections have limited treatment options. Synthesis, transport and placement of lipopolysaccharide or lipooligosaccharide (LOS) in the outer membrane of Gram-negative bacteria are important for bacterial ... ...

    Abstract Carbapenem-resistant Acinetobacter baumannii infections have limited treatment options. Synthesis, transport and placement of lipopolysaccharide or lipooligosaccharide (LOS) in the outer membrane of Gram-negative bacteria are important for bacterial virulence and survival. Here we describe the cerastecins, inhibitors of the A. baumannii transporter MsbA, an LOS flippase. These molecules are potent and bactericidal against A. baumannii, including clinical carbapenem-resistant Acinetobacter baumannii isolates. Using cryo-electron microscopy and biochemical analysis, we show that the cerastecins adopt a serpentine configuration in the central vault of the MsbA dimer, stalling the enzyme and uncoupling ATP hydrolysis from substrate flipping. A derivative with optimized potency and pharmacokinetic properties showed efficacy in murine models of bloodstream or pulmonary A. baumannii infection. While resistance development is inevitable, targeting a clinically unexploited mechanism avoids existing antibiotic resistance mechanisms. Although clinical validation of LOS transport remains undetermined, the cerastecins may open a path to narrow-spectrum treatment modalities for important nosocomial infections.
    MeSH term(s) Acinetobacter baumannii/drug effects ; Acinetobacter baumannii/metabolism ; Lipopolysaccharides/metabolism ; Animals ; Acinetobacter Infections/microbiology ; Acinetobacter Infections/drug therapy ; Mice ; Anti-Bacterial Agents/pharmacology ; Bacterial Proteins/metabolism ; Biological Transport ; Microbial Sensitivity Tests ; Humans ; Cryoelectron Microscopy ; Carbapenems/pharmacology ; Carbapenems/metabolism ; Disease Models, Animal ; Female ; ATP-Binding Cassette Transporters
    Chemical Substances Lipopolysaccharides ; lipid-linked oligosaccharides ; Anti-Bacterial Agents ; Bacterial Proteins ; MsbA protein, Bacteria ; Carbapenems ; ATP-Binding Cassette Transporters
    Language English
    Publishing date 2024-04-22
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ISSN 2058-5276
    ISSN (online) 2058-5276
    DOI 10.1038/s41564-024-01667-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Intact Human Immunodeficiency Virus (HIV) Reservoir Estimated by the Intact Proviral DNA Assay Correlates With Levels of Total and Integrated DNA in the Blood During Suppressive Antiretroviral Therapy.

    Papasavvas, Emmanouil / Azzoni, Livio / Ross, Brian N / Fair, Matthew / Yuan, Zhe / Gyampoh, Kwasi / Mackiewicz, Agnieszka / Sciorillo, Amanda C / Pagliuzza, Amelie / Lada, Steven M / Wu, Guoxin / Goh, Shih Lin / Bahnck-Teets, Carolyn / Holder, Daniel J / Zuck, Paul D / Damra, Mohammad / Lynn, Kenneth M / Tebas, Pablo / Mounzer, Karam /
    Kostman, Jay R / Abdel-Mohsen, Mohamed / Richman, Douglas / Chomont, Nicolas / Howell, Bonnie J / Montaner, Luis J

    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

    2021  Volume 72, Issue 3, Page(s) 495–498

    Abstract: Accurate characterization of the human immunodeficiency virus (HIV) reservoir is imperative to develop an effective cure. HIV was measured in antiretroviral therapy-suppressed individuals using the intact proviral DNA assay (IPDA), along with assays for ... ...

    Abstract Accurate characterization of the human immunodeficiency virus (HIV) reservoir is imperative to develop an effective cure. HIV was measured in antiretroviral therapy-suppressed individuals using the intact proviral DNA assay (IPDA), along with assays for total or integrated HIV DNA, and inducible HIV RNA or p24. Intact provirus correlated with total and integrated HIV.
    MeSH term(s) CD4-Positive T-Lymphocytes ; DNA, Viral/genetics ; HIV Infections/drug therapy ; HIV-1/genetics ; Humans ; Proviruses/genetics ; Virus Latency
    Chemical Substances DNA, Viral
    Language English
    Publishing date 2021-01-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1099781-7
    ISSN 1537-6591 ; 1058-4838
    ISSN (online) 1537-6591
    ISSN 1058-4838
    DOI 10.1093/cid/ciaa809
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1505: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
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  4. Article ; Online: A Phenotypic Screen Identifies Potent DPP9 Inhibitors Capable of Killing HIV-1 Infected Cells.

    Moore, Keith P / Schwaid, Adam G / Tudor, Matthew / Park, Sangho / Beshore, Douglas C / Converso, Antonella / Shipe, William D / Anand, Rajan / Lan, Ping / Moningka, Remond / Rothman, Deborah M / Sun, Wanying / Chi, An / Cornella-Taracido, Ivan / Adam, Gregory C / Bahnck-Teets, Carolyn / Carroll, Steven S / Fay, John F / Goh, Shih Lin /
    Lusen, Jeffrey / Quan, Shuo / Rodriguez, Silveria / Xu, Min / Andrews, Christine L / Song, Cheng / Filzen, Tracey / Li, Jing / Hollenstein, Kaspar / Klein, Daniel J / Lammens, Alfred / Lim, U-Ming / Fang, Zhiyu / McHale, Carolyn / Li, Yuan / Lu, Meiqing / Diamond, Tracy L / Howell, Bonnie J / Zuck, Paul / Balibar, Carl J

    ACS chemical biology

    2022  Volume 17, Issue 9, Page(s) 2595–2604

    Abstract: Although current antiretroviral therapy can control HIV-1 replication and prevent disease progression, it is not curative. Identifying mechanisms that can lead to eradication of persistent viral reservoirs in people living with HIV-1 (PLWH) remains an ... ...

    Abstract Although current antiretroviral therapy can control HIV-1 replication and prevent disease progression, it is not curative. Identifying mechanisms that can lead to eradication of persistent viral reservoirs in people living with HIV-1 (PLWH) remains an outstanding challenge to achieving cure. Utilizing a phenotypic screen, we identified a novel chemical class capable of killing HIV-1 infected peripheral blood mononuclear cells. Tool compounds ICeD-1 and ICeD-2 ("
    MeSH term(s) Alkynes ; Benzoxazines ; CARD Signaling Adaptor Proteins/metabolism ; Cyclopropanes ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism ; HIV Infections/drug therapy ; HIV-1/metabolism ; Humans ; Inflammasomes/metabolism ; Leukocytes, Mononuclear ; Neoplasm Proteins/metabolism
    Chemical Substances Alkynes ; Benzoxazines ; CARD Signaling Adaptor Proteins ; CARD8 protein, human ; Cyclopropanes ; Inflammasomes ; Neoplasm Proteins ; DPP9 protein, human (EC 3.4.14.-) ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (EC 3.4.14.-) ; efavirenz (JE6H2O27P8)
    Language English
    Publishing date 2022-08-31
    Publishing country United States
    Document type Journal Article
    ISSN 1554-8937
    ISSN (online) 1554-8937
    DOI 10.1021/acschembio.2c00515
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Design and Synthesis of Piperazine Sulfonamide Cores Leading to Highly Potent HIV-1 Protease Inhibitors.

    Bungard, Christopher J / Williams, Peter D / Schulz, Jurgen / Wiscount, Catherine M / Holloway, M Katharine / Loughran, H Marie / Manikowski, Jesse J / Su, Hua-Poo / Bennett, David J / Chang, Lehua / Chu, Xin-Jie / Crespo, Alejandro / Dwyer, Michael P / Keertikar, Kartik / Morriello, Gregori J / Stamford, Andrew W / Waddell, Sherman T / Zhong, Bin / Hu, Bin /
    Ji, Tao / Diamond, Tracy L / Bahnck-Teets, Carolyn / Carroll, Steven S / Fay, John F / Min, Xu / Morris, William / Ballard, Jeanine E / Miller, Michael D / McCauley, John A

    ACS medicinal chemistry letters

    2017  Volume 8, Issue 12, Page(s) 1292–1297

    Abstract: Using the HIV-1 protease binding mode ... ...

    Abstract Using the HIV-1 protease binding mode of
    Language English
    Publishing date 2017-11-13
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.7b00386
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Discovery of MK-8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group.

    Bungard, Christopher J / Williams, Peter D / Ballard, Jeanine E / Bennett, David J / Beaulieu, Christian / Bahnck-Teets, Carolyn / Carroll, Steve S / Chang, Ronald K / Dubost, David C / Fay, John F / Diamond, Tracy L / Greshock, Thomas J / Hao, Li / Holloway, M Katharine / Felock, Peter J / Gesell, Jennifer J / Su, Hua-Poo / Manikowski, Jesse J / McKay, Daniel J /
    Miller, Mike / Min, Xu / Molinaro, Carmela / Moradei, Oscar M / Nantermet, Philippe G / Nadeau, Christian / Sanchez, Rosa I / Satyanarayana, Tummanapalli / Shipe, William D / Singh, Sanjay K / Truong, Vouy Linh / Vijayasaradhi, Sivalenka / Wiscount, Catherine M / Vacca, Joseph P / Crane, Sheldon N / McCauley, John A

    ACS medicinal chemistry letters

    2016  Volume 7, Issue 7, Page(s) 702–707

    Abstract: A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of the crystal structure of the initial lead bound to HIV protease enabled optimization of enzyme potency and antiviral activity. This afforded a ...

    Abstract A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of the crystal structure of the initial lead bound to HIV protease enabled optimization of enzyme potency and antiviral activity. This afforded a series of potent orally bioavailable inhibitors of which MK-8718 was identified as a compound with a favorable overall profile.
    Language English
    Publishing date 2016-05-09
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.6b00135
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