PMID- 30932963
OWN - NLM
STAT- MEDLINE
DCOM- 20200728
LR  - 20200728
IS  - 1473-5571 (Electronic)
IS  - 0269-9370 (Linking)
VI  - 33
IP  - 10
DP  - 2019 Aug 1
TI  - Revisiting the mechanism of enfuvirtide and designing an analog with improved 
      fusion inhibitory activity by targeting triple sites in gp41.
PG  - 1545-1555
LID - 10.1097/QAD.0000000000002208 [doi]
AB  - OBJECTIVE: To revisit the mechanism of action of enfuvirtide (T20) and based on 
      the newly defined mechanism, design an analogous peptide of T20 with improved 
      antiviral activity. DESIGN: We compared the inhibitory activity of T20 with that 
      of T1144 on six-helix bundle (6HB) formation at different time after coculture of 
      HIV type 1 (HIV-1) envelope (Env)-expressing Chinese hamster ovary (CHO-Env) 
      cells and CD4-expressing MT-2 cells at 31.5  degrees C and with that of T20-SF, an 
      analogous peptide of T20 with an additional tryptophan-rich motif, on hemolysis 
      mediated by FP-P, which contains fusion peptide and fusion peptide (FP) proximal 
      region (FPPR), and HIV-1 infection. METHODS: Inhibitory activity of peptides on 
      6HB formation was tested in a temperature-controlled cell-cell fusion assay by 
      flow cytometry using 6HB-specific mAb 2G8; on HIV-1 infection and fusion was 
      assessed by p24 and cell-cell fusion assays. Interaction between different 
      peptides or peptide and antibody was evaluated by ELISA. RESULTS: T20 could 
      inhibit 6HB formation at early, but not late, stage of HIV-1 fusion, whereas 
      T1144 was effective at both stages. T20-SF is much more effective than T20 in 
      binding to FP-P and inhibiting infection of HIV-1, including T20-resistant 
      strains, and FP-P-mediated hemolysis. CONCLUSION: Results suggest that T20 has a 
      double-target mechanism, by which its N-terminal and C-terminal portions bind to 
      N-terminal heptad repeat and FPPR, respectively. T20-SF designed based on this 
      new mechanism exhibits significantly improved anti-HIV-1 activity because it 
      targets the triple sites in gp41, including N-terminal heptad repeat, FPPR, and 
      fusion peptide. Thus, this study provides clues for designing novel HIV fusion 
      inhibitors with improved antiviral activity.
FAU - Xu, Wei
AU  - Xu W
AD  - Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical 
      Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 
      China.
FAU - Pu, Jing
AU  - Pu J
AD  - Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical 
      Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 
      China.
FAU - Su, Shan
AU  - Su S
AD  - Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical 
      Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 
      China.
FAU - Hua, Chen
AU  - Hua C
AD  - Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical 
      Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 
      China.
FAU - Su, Xiaojie
AU  - Su X
AD  - Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical 
      Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 
      China.
FAU - Wang, Qian
AU  - Wang Q
AD  - Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical 
      Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 
      China.
FAU - Jiang, Shibo
AU  - Jiang S
AD  - Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical 
      Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 
      China.
AD  - Lindsley F. Kimball Research Institute, New York Blood Center, New York, New 
      York, USA.
FAU - Lu, Lu
AU  - Lu L
AD  - Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical 
      Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 
      China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - AIDS
JT  - AIDS (London, England)
JID - 8710219
RN  - 0 (HIV Core Protein p24)
RN  - 0 (HIV Envelope Protein gp41)
RN  - 0 (HIV Fusion Inhibitors)
RN  - 0 (Recombinant Proteins)
RN  - 0 (gp41 protein, Human immunodeficiency virus 1)
RN  - 19OWO1T3ZE (Enfuvirtide)
SB  - IM
MH  - Animals
MH  - Binding Sites
MH  - Cell Fusion
MH  - Cell Line
MH  - Drug Discovery/*methods
MH  - Enfuvirtide/chemical synthesis/*chemistry/*pharmacology
MH  - HIV Core Protein p24/metabolism
MH  - HIV Envelope Protein gp41/*chemistry/*metabolism
MH  - HIV Fusion Inhibitors/chemical synthesis/*chemistry/*pharmacology
MH  - Humans
MH  - Protein Binding
MH  - Recombinant Proteins/chemistry/metabolism
MH  - Temperature
EDAT- 2019/04/02 06:00
MHDA- 2020/07/29 06:00
CRDT- 2019/04/02 06:00
PHST- 2019/04/02 06:00 [pubmed]
PHST- 2020/07/29 06:00 [medline]
PHST- 2019/04/02 06:00 [entrez]
AID - 10.1097/QAD.0000000000002208 [doi]
PST - ppublish
SO  - AIDS. 2019 Aug 1;33(10):1545-1555. doi: 10.1097/QAD.0000000000002208.