HIV-1 capsid protein(CA) has emerged as a promising target for antiviral treatment considering its structural and regulatory roles in HIV-1 replication. Here, we disclose the design, synthesis, biological assessment, ...HIV-1 capsid protein(CA) has emerged as a promising target for antiviral treatment considering its structural and regulatory roles in HIV-1 replication. Here, we disclose the design, synthesis, biological assessment, and mechanism investigation of a novel series of phenylalanine derivatives gained by further structural modification of PF74. The newly synthesized compounds demonstrated potent anti-HIV activity, represented by 7n displayed anti-HIV-1 activity 6.25-fold better than PF74, and 7h showed anti-HIV-2activity with nearly 139 times improved efficacy over PF74. Surface plasmon resonance(SPR) studies of representative compounds proved that HIV-1 CA was the binding target. Competitive SPR studies using CPSF6 and NUP153 peptides identified that 7n binds to a vital CA assembly interface between the Nterminal and C-terminal domain(NTD-CTD interface). Action stage determination assay revealed that the newly synthesized compounds were antiviral with a dual-stage inhibitory profile. Molecular dynamics(MD) simulations offered the crucial foundation for the hopeful antiviral potency of 7n. Besides, 7m and7n modestly increased metabolic stabilities in human liver microsome(HLM) and human plasma compared to PF74. Overall, these studies offer valuable insights and can regard as the beginning for succedent medicinal chemistry endeavors to discover promising HIV capsid inhibitors with improved efficacy and better drug-like characteristics.展开更多
基金financial support from the National Natural Science Foundation of China(NSFC,Nos.82173677,81773574)the Key Project of NSFC for International Cooperation(No.81420108027)+2 种基金the Shandong Provincial Key Research and Development Project(No.2019JZZY021011)the Science Foundation for Outstanding Young Scholars of Shandong Province(No.ZR2020JQ31)NIH/NIAID grant(No.R01AI150491,Cocklin,PI,Salvino,Co-I)。
文摘HIV-1 capsid protein(CA) has emerged as a promising target for antiviral treatment considering its structural and regulatory roles in HIV-1 replication. Here, we disclose the design, synthesis, biological assessment, and mechanism investigation of a novel series of phenylalanine derivatives gained by further structural modification of PF74. The newly synthesized compounds demonstrated potent anti-HIV activity, represented by 7n displayed anti-HIV-1 activity 6.25-fold better than PF74, and 7h showed anti-HIV-2activity with nearly 139 times improved efficacy over PF74. Surface plasmon resonance(SPR) studies of representative compounds proved that HIV-1 CA was the binding target. Competitive SPR studies using CPSF6 and NUP153 peptides identified that 7n binds to a vital CA assembly interface between the Nterminal and C-terminal domain(NTD-CTD interface). Action stage determination assay revealed that the newly synthesized compounds were antiviral with a dual-stage inhibitory profile. Molecular dynamics(MD) simulations offered the crucial foundation for the hopeful antiviral potency of 7n. Besides, 7m and7n modestly increased metabolic stabilities in human liver microsome(HLM) and human plasma compared to PF74. Overall, these studies offer valuable insights and can regard as the beginning for succedent medicinal chemistry endeavors to discover promising HIV capsid inhibitors with improved efficacy and better drug-like characteristics.
