DDX3X inhibitors, an effective way to overcome HIV-1 resistance targeting host proteins

被引：30

作者：

Brai, Annalaura ^{[1
]}

Riva, Valentina ^{[2
]}

Saladini, Francesco ^{[3
]}

Zamperini, Claudio ^{[1
]}

Trivisani, Claudia Immacolata ^{[1
]}

Garbelli, Anna ^{[2
]}

Pennisi, Carla ^{[2
]}

Giannini, Alessia ^{[3
]}

Boccuto, Adele ^{[3
]}

Bugli, Francesca ^{[4
,5
]}

Martini, Maurizio ^{[6
,7
]}

Sanguinetti, Maurizio ^{[4
,5
]}

Zazzi, Maurizio ^{[3
]}

Dreassi, Elena ^{[1
]}

Botta, Maurizio ^{[1
,8
]}

Maga, Giovanni ^{[2
]}

机构：

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

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

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

[4] Fdn Policlin Univ A Gemelli IRCCS, Dipartimento Sci Lab & Infettivol, I-00168 Rome, Italy

[5] Univ Cattolica SC, Ist Microbiol, Lgo F Vito 1, I-00168 Rome, Italy

[6] Fdn Policlin Univ A Gemelli IRCCS, Serv Istopatol & Citodiag, Rome, Italy

[7] Univ Cattolica Sacro Cuore, Ist Patol, Rome, Italy

[8] Temple Univ, Coll Sci & Technol, Ctr Biotechnol, Sbarro Inst Canc Res & Mol Med, BioLife Sci Bldg,Suite 333,1900 N 12th St, Philadelphia, PA 19122 USA

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 200卷

关键词：

DDX3X; Host factors; HIV-1; Antiviral agents; Drug resistance; Coinfections; DRUG-RESISTANCE; RNA HELICASE; DISCOVERY; ROLES;

D O I：

10.1016/j.ejmech.2020.112319

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The huge resources that had gone into Human Immunodeficiency virus (HIV) research led to the development of potent antivirals able to suppress viral load in the majority of treated patients, thus dramatically increasing the life expectancy of people living with HIV. However, life-long treatments could result in the emergence of drug-resistant viruses that can progressively reduce the number of therapeutic options, facilitating the progression of the disease. In this scenario, we previously demonstrated that inhibitors of the human DDX3X helicase can represent an innovative approach for the simultaneous treatment of HIV and other viral infections such as Hepatitis c virus (HCV). We reported herein 6b, a novel DDX3X inhibitor that thanks to its distinct target of action is effective against HIV-1 strains resistant to currently approved drugs. Its improved in vitro ADME properties allowed us to perform preliminary in vivo studies in mice, which highlighted optimal biocompatibility and an improved bioavailability. These results represent a significant advancement in the development of DDX3X inhibitors as a novel class of broad spectrum and safe anti-HIV-1 drugs. (C) 2020 The Authors. Published by Elsevier Masson SAS.

引用

页数：12

共 33 条

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