Synthesis and Antiviral Activity of Novel 1,3,4-Thiadiazole Inhibitors of DDX3X

被引：33

作者：

Brai, Annalaura ^{[1
]}

Ronzini, Stefania ^{[1
]}

Riva, Valentina ^{[2
]}

Botta, Lorenzo ^{[1
]}

Zamperini, Claudio ^{[1
]}

Borgini, Matteo ^{[1
]}

Trivisani, Claudia Immacolata ^{[1
]}

Garbelli, Anna ^{[2
]}

Pennisi, Carla ^{[2
]}

Boccuto, Adele ^{[3
]}

Saladini, Francesco ^{[3
]}

Zazzi, Maurizio ^{[3
]}

Maga, Giovanni ^{[2
]}

Botta, Maurizio ^{[1
,4
]}

机构：

[1] Univ Siena, Dipartimento Biotecnol Chim & Farm, Via A Moro 2, I-53100 Siena, Italy

[2] IGM CNR Luigi Luca Cavalli Sforza, Ist Genet Mol, Via Abbiategrasso 207, I-27100 Pavia, Italy

[3] Univ Siena, Dipartimento Biotecnol Med, I-53100 Siena, Italy

[4] Temple Univ, Biotechnol Coll Sci & Technol, BioLife Sci Bldg,Suite 333,1900 North 12th St, Philadelphia, PA 19122 USA

来源：

MOLECULES | 2019年 / 24卷 / 21期

关键词：

DDX3X; HIV-1; host proteins; antivirals; HEPATITIS-C VIRUS; BOX RNA HELICASE; SMALL-MOLECULE INHIBITOR; REPLICATION; DISCOVERY; TARGET;

D O I：

10.3390/molecules24213988

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The human ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against both infectious diseases and cancer. Herein, a new family of DDX3X inhibitors was designed, synthesized, and tested for its inhibitory action on the ATPase activity of the enzyme. The potential use of the most promising derivatives it has been investigated by evaluating their anti-HIV-1 effects, revealing inhibitory activities in the low micromolar range. A preliminary ADME analysis demonstrated high metabolic stability and good aqueous solubility. The promising biological profile, together with the suitable in vitro pharmacokinetic properties, make these novel compounds a very good starting point for further development.

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页数：18

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共 26 条

[1] DDX3 DEAD-box RNA helicase is required for hepatitis C virus RNA replication [J].

Ariumi, Yasuo ;

Kuroki, Misao ;

Abe, Ken-ichi ;

Dansako, Hiromichi ;

Ikeda, Masanori ;

Wakita, Takaji ;

Kato, Nobuyuki .

JOURNAL OF VIROLOGY, 2007, 81 (24) :13922-13926

[2] New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays [J].

Baell, Jonathan B. ;

Holloway, Georgina A. .

JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (07) :2719-2740

[3] Targeting DDX3 with a small molecule inhibitor for lung cancer therapy [J].

Bol, Guus M. ;

Vesuna, Farhad ;

Xie, Min ;

Zeng, Jing ;

Aziz, Khaled ;

Gandhi, Nishant ;

Levine, Anne ;

Irving, Ashley ;

Korz, Dorian ;

Tantravedi, Saritha ;

van Voss, Marise R. Heerma ;

Gabrielson, Kathleen ;

Bordt, Evan A. ;

Polster, Brian M. ;

Cope, Leslie ;

van der Groep, Petra ;

Kondaskar, Atul ;

Rudek, Michelle A. ;

Hosmane, Ramachandra S. ;

van der Wall, Elsken ;

van Diest, Paul J. ;

Tran, Phuoc T. ;

Raman, Venu .

EMBO MOLECULAR MEDICINE, 2015, 7 (05) :648-669

[4] DDX3X Helicase Inhibitors as a New Strategy To Fight the West Nile Virus Infection [J].

Brai, Annalaura ;

Martelli, Francesco ;

Riva, Valentina ;

Garbelli, Anna ;

Fazi, Roberta ;

Zamperini, Claudio ;

Pollutri, Alessandro ;

Falsitta, Lucia ;

Ronzini, Stefania ;

Maccari, Laura ;

Maga, Giovanni ;

Giannecchini, Simone ;

Botta, Maurizio .

JOURNAL OF MEDICINAL CHEMISTRY, 2019, 62 (05) :2333-2347

[5] Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents [J].

Brai, Annalaura ;

Fazi, Roberta ;

Tintori, Cristina ;

Zamperini, Claudio ;

Bugli, Francesca ;

Sanguinetti, Maurizio ;

Stigliano, Egidio ;

Este, Jose ;

Badia, Roger ;

Franco, Sandra ;

Martinez, Miguel A. ;

Martinez, Javier P. ;

Meyerhans, Andreas ;

Saladini, Francesco ;

Zazzi, Maurizio ;

Garbelli, Anna ;

Maga, Giovanni ;

Botta, Maurizio .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2016, 113 (19) :5388-5393

[6] P-body components LSM1, GW182, DDX3, DDX6 and XRN1 are recruited to WNV replication sites and positively regulate viral replication [J].

Chahar, Harendra S. ;

Chen, Shuiping ;

Manjunath, N. .

VIROLOGY, 2013, 436 (01) :1-7

[7] Homology Model-Based Virtual Screening for the Identification of Human Helicase DDX3 Inhibitors [J].

Fazi, Roberta ;

Tintori, Cristina ;

Brai, Annalaura ;

Botta, Lorenzo ;

Selvaraj, Manikandan ;

Garbelli, Anna ;

Maga, Giovanni ;

Botta, Maurizio .

JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2015, 55 (11) :2443-2454

[8] Crystal structure of conserved domains 1 and 2 of the human DEAD-box helicase DDX3X in complex with the mononucleotide AMP [J].

Hogbom, Martin ;

Collins, Ruairi ;

van den Berg, Susanne ;

Jenvert, Rose-Marie ;

Karlberg, Tobias ;

Kotenyova, Tetyana ;

Flores, Alex ;

Hedestam, Gunilla B. Karlsson ;

Schiavone, Lovisa Holmberg .

JOURNAL OF MOLECULAR BIOLOGY, 2007, 372 (01) :150-159

[9] Knockdown of cellular RNA helicase DDX3 by short hairpin RNAs suppresses HIV-1 viral replication without inducing apoptosis [J].

Ishaq, Musarat ;

Hu, Jiajie ;

Wu, Xiaoyun ;

Fu, Qiong ;

Yang, Yalin ;

Liu, Qingzhen ;

Guo, Deyin .

MOLECULAR BIOTECHNOLOGY, 2008, 39 (03) :231-238

[10] Novel, Broad Spectrum Anticancer Agents Containing the Tricyclic 5:7:5-Fused Diimidazodiazepine Ring System [J].

Kondaskar, Atul ;

Kondaskar, Shilpi ;

Kumar, Raj ;

Fishbein, James C. ;

Muvarak, Nidal ;

Lapidus, Rena G. ;

Sadowska, Mariola ;

Edelman, Martin J. ;

Bol, Guus M. ;

Vesuna, Farhad ;

Raman, Venu ;

Hosmane, Ramachandra S. .

ACS MEDICINAL CHEMISTRY LETTERS, 2011, 2 (03) :252-256