Discovery and Characterization of a Novel CD4-Binding Adnectin with Potent Anti-HIV Activity

被引：0
作者：
Wensel, David [1 ,3 ]
Sun, Yongnian [2 ]
Li, Zhufang [2 ,3 ]
Zhang, Sharon [2 ,3 ]
Picarillo, Caryn [1 ]
McDonagh, Thomas [1 ]
Fabrizio, David [2 ]
Cockett, Mark [2 ,3 ]
Krystal, Mark [2 ,3 ]
Davis, Jonathan [1 ,4 ]
机构：
[1] Bristol Myers Squibb, Dept Mol Discovery Technol, Waltham, MA 02453 USA
[2] Bristol Myers Squibb, Dept Virol, Wallingford, CT USA
[3] ViiV Healthcare, Wallingford, CT 06492 USA
[4] Fdn Med, Cambridge, MA USA
来源：
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY | 2017年 / 61卷 / 08期
关键词：
Adnectin; CD4; N17; gp41; HIV inhibitor; human immunodeficiency virus; MONOCLONAL-ANTIBODY; CRYSTAL-STRUCTURE; III DOMAIN; ANTI-HIV-1; ACTIVITY; CD4; RECEPTOR; HALF-LIFE; PRO; 140; FIBRONECTIN; BINDING; INHIBITOR;
D O I：
10.1128/AAC.00508-17
中图分类号：
Q93 [微生物学];
学科分类号：
071005 ; 100705 ;
摘要：
A novel fibronectin-based protein (Adnectin) HIV-1 inhibitor was generated using in vitro selection. This inhibitor binds to human CD4 with a high affinity (3.9 nM) and inhibits viral entry at a step after CD4 engagement and preceding membrane fusion. The progenitor sequence of this novel inhibitor was selected from a library of trillions of Adnectin variants using mRNA display and then further optimized for improved antiviral and physical properties. The final optimized inhibitor exhibited full potency against a panel of 124 envelope (gp160) proteins spanning 11 subtypes, indicating broad-spectrum activity. Resistance profiling studies showed that this inhibitor required 30 passages (151 days) in culture to acquire sufficient resistance to result in viral titer breakthrough. Resistance mapped to the loss of multiple potential N-linked glycosylation sites in gp120, suggesting that inhibition is due to steric hindrance of CD4-binding-induced conformational changes.
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页数：19
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