Discovery of dual inhibitors targeting both HIV-1 capsid and human cyclophilin A to inhibit the assembly and uncoating of the viral capsid

Li, Jiebo; Tan, Zhiwu; Tang, Shixing; Hewlett, Indira; Pang, Ruifang; He, Meizi; He, Shanshan; Tian, Baohe; Chen, Kan; Yang, Ming

doi:10.1016/j.bmc.2009.02.051

Cited by 40 publications

(36 citation statements)

References 27 publications

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“…Cyclophilin A is a cytosolic protein that exhibits isoprolyl isomerase activity and interacts with the HIV-1 capsid protein (42)(43)(44)(45)(46). Cyclophilin A is believed to modulate the disassembly process of the HIV-1 core (47).…”

Section: Figmentioning

confidence: 99%

Human Cytosolic Extracts Stabilize the HIV-1 Core

Fricke

Brandariz-Núñez

Wang

et al. 2013

J Virol

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bThe stability of the HIV-1 core in the cytoplasm is crucial for productive HIV-1 infection. Mutations that stabilize or destabilize the core showed defects on HIV-1 reverse transcription and infection. We developed a novel and simple assay to measure the stability of in vitro-assembled HIV-1 CA-NC complexes. The assay allowed us to demonstrate that cytosolic extracts strongly stabilize the HIV-1 core. Interestingly, stabilization of in vitro-assembled HIV-1 CA-NC complexes is not due solely to macromolecular crowding, suggesting the presence of specific cellular factors that stabilize the HIV-1 core. By using our novel assay, we measured the abilities of different drugs, such as PF74, CAP-1, IXN-053, cyclosporine, Bi2 (also known as BI-2), and the peptide CAI, to modulate the stability of in vitro-assembled HIV-1 CA-NC complexes. Interestingly, we found that PF74 and Bi2 strongly stabilized HIV-1 CA-NC complexes. On the other hand, the peptide CAI destabilized HIV-1 CA-NC complexes. We also found that purified cyclophilin A destabilizes in vitro-assembled HIV-1 CA-NC complexes in the presence of cellular extracts in a cyclosporine-sensitive manner. In agreement with previous observations using the fate-of-the-capsid assay, we also demonstrated the ability of recombinant CPSF6 to stabilize HIV-1 CA-NC complexes. Overall, our findings suggested that cellular extracts specifically stabilize the HIV-1 core. We believe that our assay can be a powerful tool to assess HIV-1 core stability in vitro.

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Section: Figmentioning

confidence: 99%

Human Cytosolic Extracts Stabilize the HIV-1 Core

Fricke

Brandariz-Núñez

Wang

et al. 2013

J Virol

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“…However, a rapidly growing body of evidence demonstrates multiple potentially beneficial biological activities of its derivatives. Some of these compounds show potential as prodrugs of the alcohol deterrent agent cyanamide (Shirota et al, 1997), inhibitors of HIV capsid assembly (Li et al, 2009b), blockers of the CXCR4 chemokine receptors with potential for preventing HIV infection of target cells (Thoma et al, 2008), anticancer drugs (for review see Li et al, 2009a), hypoglycaemic drugs (Zhang et al, 2009), calcium blockers with potential neuroprotectant and cognition enhancer capability (Perlovich et al, 2009), anti-HCV agents with high selectivity index (Kang et al, 2009), and proapoptotic agents with substantial toxicity toward human glioblastoma cells in vitro (Kaminska et al, 2009). However, most attention is being given to these drugs as nitric oxide synthase (NOS) inhibitors with variable NOS isoform selectivity (Szabo et al, 1994;Southan et al, 1995;Handy et al, 1996;Wang et al, 1998;Paquay et al, 1999;Ijuin et al, 2005;Jin et al, 2009) and antimicrobial agents.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antimicrobial and nitric oxide synthase inhibitory activities of novel isothiourea derivatives

et al. 2010

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The reaction of substituted benzylhalides, or of halomethyl derivatives of thiophene or furane, with thiourea or its derivatives yielded the respective isothioureas as hydrohalide salts. The products (a total of 17, including 16 novel compounds) were tested for activity against five Gram-positive and nine Gram-negative bacterial strains, six yeast species and two protozoan species. The most active against Gram-positive bacteria were S-(2,4-dinitrobenzyl)isothiourea hydrochloride (MIC range for four out of five strains tested: 12.5-25 microg/mL) and S-(2,3,4,5,6-pentabromobenzyl)isothiourea hydrobromide (MIC range: 12.5-50 microg/mL). The lowest MICs of novel isothioureas for yeast and Gram-negative bacteria ranged between 50 and 100 microg/mL. Nine novel isothioureas showed appreciable genotoxicity in the Bacillus subtilis 'rec-assay' test, the most potent being S-2-(5-nitrofuran-2-ylmethyl)isothiourea and S-(2-nitrobenzyl) isothiourea. At 10 muM concentration, S-(3,4-dichlorobenzyl)isothiourea hydrochloride and S-(2,3,4,5,6-pentabromobenzyl)isothiourea hydrobromide inhibited Ca(2+)/calmodulin-dependent (non-inducible) nitric oxide synthase activity in normal rat brain homogenates stronger (p < 0.05) than the reference drug 7-nitroindazole (by 78, 76 and 60%, respectively); ten other new isothiourea derivatives significantly inhibited the activity to a lower extent (by 28-60%). These results extend the list of promising isothioureas with substantial activity in vitro and suggest that an in-depth study of toxicity, antimicrobial properties in vivo and nitric oxide synthase isoform selectivity of selected novel compounds is warranted.

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“…The CypA-CA interaction within the target cell specifically promotes infectivity, and disrupting this interaction leads to a decrease in infectivity in certain cell types (49,58,67). Though the specific mechanism governing the uncoating step has not been fully elucidated, the process of uncoating and the major viral and host factors involved in the uncoating step, such as CA and CypA, have been investigated as new drug targets (2,32,33,68).…”

mentioning

confidence: 99%

Role of Human Immunodeficiency Virus Type 1 Integrase in Uncoating of the Viral Core

Briones¹,

Dobard²,

Chow³

2010

J Virol

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After membrane fusion with a target cell, the core of human immunodeficiency virus type 1 (HIV-1) enters into the cytoplasm, where uncoating occurs. The cone-shaped core is composed of the viral capsid protein (CA), which disassembles during uncoating. The underlying factors and mechanisms governing uncoating are poorly understood. Several CA mutations can cause changes in core stability and a block at reverse transcription, demonstrating the requirement for optimal core stability during viral replication. HIV-1 integrase (

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Discovery of dual inhibitors targeting both HIV-1 capsid and human cyclophilin A to inhibit the assembly and uncoating of the viral capsid

Cited by 40 publications

References 27 publications

Human Cytosolic Extracts Stabilize the HIV-1 Core

Human Cytosolic Extracts Stabilize the HIV-1 Core

Synthesis and antimicrobial and nitric oxide synthase inhibitory activities of novel isothiourea derivatives

Role of Human Immunodeficiency Virus Type 1 Integrase in Uncoating of the Viral Core

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