1,4-Bis(5-(naphthalen-1-yl)thiophen-2-yl)naphthalene, a small molecule, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular Lens epithelium-derived growth factor

• Published in: Chemico-biological interactions Vol. 213; pp. 21 - 27
• Main Authors: Gu, Wan-gang, Ip, Denis Tsz-Ming, Liu, Si-jie, Chan, Joseph H., Wang, Yan, Zhang, Xuan, Zheng, Yong-tang, Wan, David Chi-Cheong
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 25.04.2014
• Subjects: Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Delivery Systems; HIV Integrase - chemistry; HIV Integrase - metabolism; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 integrase; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Inhibitory Concentration 50; Intercellular Signaling Peptides and Proteins - chemistry; Intercellular Signaling Peptides and Proteins - metabolism; Lens epithelium-derived growth factor (LEDGF/P75); Models, Molecular; Molecular docking; Molecular Docking Simulation; Naphthalenes - chemistry; Naphthalenes - pharmacology; Small Molecule Libraries; Thiophenes - chemistry; Thiophenes - pharmacology; Virus Replication - drug effects; Lens epithelium-derived growth factor (LEDGF/P75); HIV-1 integrase; Molecular docking
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2014.01.011

•Compound 15 potently inhibited the HIV-1 IN nuclear translocation at 1μM.•The binding mode of Compound 15 provided valuable information for drug design.•Compound 15 suppressed HIV-1 p24 antigen production with an EC50 value of 11.19μM. Translocation of viral integrase (IN) into the nucleus is a critical precondition of integration during the life cycle of HIV, a causative agent of Acquired Immunodeficiency Syndromes (AIDS). As the first discovered cellular factor to interact with IN, Lens epithelium-derived growth factor (LEDGF/p75) plays an important role in the process of integration. Disruption of the LEDGF/p75-IN interaction has provided a great interest for anti-HIV agent discovery. In this work, we reported that one small molecular compound, 1,4-bis(5-(naphthalen-1-yl)thiophen-2-yl)naphthalene(Compound 15), potently inhibit the IN-LEDGF/p75 interaction and affect the HIV-1 IN nuclear distribution at 1μM. The putative binding mode of Compound 15 was constructed by a molecular docking simulation to provide structural insights into the ligand-binding mechanism. Compound 15 suppressed viral replication by measuring p24 antigen production in HIV-1IIIB acute infected C8166 cells with EC50 value of 11.19μM. Compound 15 might supply useful structural information for further anti-HIV agent discovery.