Meizi He

Design, synthesis, and biological evaluation of novel quinoline derivatives as HIV-1 Tat-TAR interaction inhibitors.

Thirty-two quinoline derivatives were designed and synthesized as HIV-1 Tat-TAR interaction inhibitors. All the compounds showed high antiviral activities in inhibiting the formation of SIV-induced syncytium in CEM174 cells. Nine of them with low cytotoxicities were evaluated by Tat dependent HIV-1 LTR-driven CAT gene expression colorimetric enzyme assay in human 293T cells, indicating effective inhibitory activities of blocking the Tat-TAR interaction. Molecular modeling experiments indicated that these compounds may inhibit Tat-TAR interaction by binding to Tat protein instead of TAR RNA.

Synthesis and antiviral activities of novel acylhydrazone derivatives targeting HIV-1 capsid protein

HIV-1 capsid protein (CA) plays important roles in the viral replication cycle. A number of acylhydrazone derivatives that act as inhibitors of HIV-1 CA assembly, were designed and synthesized. The synthesized compounds were tested for their antiviral activities and cytotoxicities using CEM cells. Some derivatives also were assayed for their ability to inhibit HIV-1 CA assembly in vitro. Among them, compounds 14f and 14i display the most promising potency with EC(50) values of 0.21 and 0.17 microM respectively.

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

HIV-1 assembly and disassembly (uncoating) processes are critical for the HIV-1 replication. HIV-1 capsid (CA) and human cyclophilin A (CypA) play essential roles in these processes. We designed and synthesized a series of thiourea compounds as HIV-1 assembly and disassembly dual inhibitors targeting both HIV-1 CA protein and human CypA. The SIV-induced syncytium antiviral evaluation indicated that all of the inhibitors displayed antiviral activities in SIV-infected CEM cells at the concentration of 0.6-15.8 microM for 50% of maximum effective rate. Their abilities to bind CA and CypA were determined by ultraviolet spectroscopic analysis, fluorescence binding affinity and PPIase inhibition assay. Assembly studies in vitro demonstrated that the compounds could potently disrupt CA assembly with a dose-dependent manner. All of these molecules could bind CypA with binding affinities (Kd values) of 51.0-512.8 microM. Fifteen of the CypA binding compounds showed potent PPIase inhibitory activities (IC(50) values<1 microM) while they could not bind either to HIV-1 Protease or to HIV-1 Integrase in the enzyme assays. These results suggested that 15 compounds could block HIV-1 replication by inhibiting the PPIase activity of CypA to interfere with capsid disassembly and disrupting CA assembly.

Synthesis and Antiviral Evaluation of New N‐acylhydrazones Containing Glycine Residue

N‐acylhydrazones containing glycine residue 3a–j and 8a–h were synthesized as HIV‐1 capsid protein assembly inhibitors. The structures of the novel N‐acylhydrazone derivatives were characterized using different spectroscopic methods. Antiviral activity demonstrated that compound 8c bearing 4‐methylphenyl moiety was the most active with low cytotoxicity.

Structure–Activity Relationships (SAR) Research of Thiourea Derivatives as Dual Inhibitors Targeting both HIV-1 Capsid and Human Cyclophilin A

HIV‐1 capsid (CA) and human cyclophilin A (CypA) play important roles in HIV‐1 assembly and disassembly processes, which are critical in HIV‐1 replication. Based on the discovery of thiourea derivatives targeting both of the two proteins and indicating effective inhibitory activities in our group, we designed and synthesized a new class of thiourea derivatives. Their abilities to bind to capsid and cyclophilin A were determined by ultraviolet spectroscopic analysis, fluorescence binding affinity, and PPIase inhibition assay. Furthermore, the newly synthesized compounds were tested for their antiviral activities and cytotoxicities using CEM cells. According to the biological evaluation and subsequent molecular docking analyses, we studied the structure–activity relationships of thiourea derivatives. Three optimal compounds (K17, K24, K25) based on the achieved structure–activity relationships would be the basis for future optimization.

Design, synthesis, and biological evaluation of novel substituted [1,2,3]triazolo[4,5‑ d ]pyrimidines as HIV-1 Tat-TAR interaction inhibitors

A novel series of compounds, derived from [1,2,3]triazolo[4,5-d]pyrimidines with a guanidyl group or amino group-terminated side chain was designed and synthesized as HIV-1 trans-activator of transcription–trans-activation responsive region (Tat–TAR) interaction inhibitors. Their ability to inhibit Tat–TAR RNA interaction was determined by a Tat-dependent HIV-1 long terminal repeat (LTR)-driven chloramphenicol acetyltransferase (CAT) assay and simian immunodeficiency virus (SIV)-induced syncytium evaluation. The binding of the compounds with TAR RNA was conducted by molecular modeling and capillary electrophoresis (CE) analysis. The results showed that all the compounds could block the Tat–TAR interaction and have antiviral activities.