title: Site-specific Isopeptide Bridge Tethering of Chimeric gp41 N-terminal Heptad Repeat Helical Trimers for the Treatment of HIV-1 Infection.
abstract: Peptides derived from the N-terminal heptad repeat (NHR) of HIV-1 gp41 can be potent inhibitors against viral entry when presented in a nonaggregating trimeric coiled-coil conformation via the introduction of exogenous trimerization motifs and intermolecular disulfide bonds. We recently discovered that crosslinking isopeptide bridges within the de novo helical trimers added exceptional resistance to unfolding. Herein, we attempted to optimize (CCIZN17)3, a representative disulfide bond-stabilized chimeric NHR-trimer, by incorporating site-specific interhelical isopeptide bonds as the redox-sensitive disulfide surrogate. In this process, we systematically examined the effect of isopeptide bond position and molecular sizes of auxiliary trimeric coiled-coil motif and NHR fragments on the antiviral potency of these NHR-trimers. Pleasingly, (IZ14N24N)3 possessed promising inhibitory activity against HIV-1 infection and markedly increased proteolytic stability relative to its disulfide-tethered counterpart, suggesting good potential for further development as an effective antiviral agent for treatment of HIV-1 infection.
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology &Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.
authors: Chao
authors: C
authors: Wang
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology &Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.
authors: Xue
authors: X
authors: Li
authors: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors: Fei
authors: F
authors: Yu
authors: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors: Lu
authors: L
authors: Lu
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology &Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.
authors: Xifeng
authors: X
authors: Jiang
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology &Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.
authors: Xiaoyu
authors: X
authors: Xu
authors: School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China.
authors: Huixin
authors: H
authors: Wang
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology &Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.
authors: Wenqing
authors: W
authors: Lai
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology &Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.
authors: Tianhong
authors: T
authors: Zhang
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology &Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.
authors: Zhenqing
authors: Z
authors: Zhang
authors: Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Ling
authors: L
authors: Ye
authors: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.|Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.
authors: Shibo
authors: S
authors: Jiang
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology &Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.
authors: Keliang
authors: K
authors: Liu
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D008297:Male; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000998:Antiviral Agents; D015700:HIV Envelope Protein gp41; D010455:Peptides; C514787:gp41 protein, Human immunodeficiency virus 1