MersV1, Main, Exploration, bibRecord, 000E45

Creating an Artificial Tail Anchor as a Novel Strategy To Enhance the Potency of Peptide-Based HIV Fusion Inhibitors.

Identifieur interne : 000E45 ( Main/Exploration ); précédent : 000E44; suivant : 000E46

Creating an Artificial Tail Anchor as a Novel Strategy To Enhance the Potency of Peptide-Based HIV Fusion Inhibitors.

Source :

Journal of virology [ 1098-5514 ] ; 2017.

RBID : pubmed:27795416

Descripteurs français

English descriptors

KwdEn :
- Amino Acid Sequence, Cell Line, Tumor, Crystallography, X-Ray, Drug Design, Enfuvirtide, HIV Envelope Protein gp41 (chemical synthesis), HIV Envelope Protein gp41 (pharmacology), HIV Fusion Inhibitors (chemical synthesis), HIV Fusion Inhibitors (pharmacology), HIV-1 (chemistry), HIV-1 (drug effects), HIV-1 (growth & development), HIV-1 (metabolism), Humans, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Neuroglia (drug effects), Neuroglia (immunology), Neuroglia (virology), Peptide Fragments (chemical synthesis), Peptide Fragments (pharmacology), Protein Interaction Domains and Motifs, Protein Multimerization, Protein Structure, Secondary, Sequence Alignment, Structure-Activity Relationship, T-Lymphocytes (drug effects), T-Lymphocytes (immunology), T-Lymphocytes (virology), Virus Internalization (drug effects).
MESH :
- chemical , chemical synthesis : HIV Envelope Protein gp41, HIV Fusion Inhibitors, Peptide Fragments.
- chemical , pharmacology : HIV Envelope Protein gp41, HIV Fusion Inhibitors, Peptide Fragments.
- chemical : Enfuvirtide.
- chemistry : HIV-1.
- drug effects : HIV-1, Neuroglia, T-Lymphocytes, Virus Internalization.
- growth & development : HIV-1.
- immunology : Neuroglia, T-Lymphocytes.
- metabolism : HIV-1.
- virology : Neuroglia, T-Lymphocytes.
- Amino Acid Sequence, Cell Line, Tumor, Crystallography, X-Ray, Drug Design, Humans, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Structure, Secondary, Sequence Alignment, Structure-Activity Relationship.

Abstract

20 (enfuvirtide) and other peptides derived from the human immunodeficiency virus type 1 (HIV-1) gp41 C-terminal heptad repeat (CHR) region inhibit HIV fusion by binding to the hydrophobic grooves on the N-terminal heptad repeat (NHR) trimer and blocking six-helix-bundle (6-HB) formation. Several strategies focusing on the binding grooves of the NHR trimer have been adopted to increase the antiviral activity of the CHR peptides. Here, we developed a novel and simple strategy to greatly enhance the potency of the existing peptide-based HIV fusion inhibitors. First, we identified a shallow pocket adjacent to the groove in the N-terminal region of NHR trimer as a new drug target, and then we designed several short artificial peptides to fit this target. After the addition of IDL (Ile-Asp-Leu) to the C terminus of CHR peptide WQ or MT-WQ, the conjugated peptides, WQ-IDL and MT-WQ-IDL, showed much more potent activities than WQ and T20, respectively, in inhibiting HIV-1 IIIB infection. WQ-IDL and MT-WQ-IDL were also more effective than WQ in blocking HIV-1 Env-mediated membrane fusion and had higher levels of binding affinity with NHR peptide N46. We solved the crystal structure of the 6-HB formed by MT-WQ-IDL and N46 and found that, besides the N-terminal MT hook tail, the IDL tail anchor of MT-WQ-IDL also binds with the shallow hydrophobic pocket outside the groove of the NHR trimer, resulting in enhanced inhibition of HIV-1 fusion with the target cell. It is expected that this novel approach can be widely used to improve the potency of peptidic fusion inhibitors against other enveloped viruses with class I fusion proteins.

DOI: 10.1128/JVI.01445-16
PubMed: 27795416

Affiliations:

Le document en format XML

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<author><name sortKey="Wang, Qian" sort="Wang, Qian" uniqKey="Wang Q" first="Qian" last="Wang">Qian Wang</name>
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<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai</wicri:regionArea>
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<author><name sortKey="Zhang, Rongguang" sort="Zhang, Rongguang" uniqKey="Zhang R" first="Rongguang" last="Zhang">Rongguang Zhang</name>
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<wicri:regionArea>National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing</wicri:regionArea>
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<author><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name>
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<country wicri:rule="url">République populaire de Chine</country>
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<wicri:noRegion>Shanghai</wicri:noRegion>
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</author>
<author><name sortKey="Lu, Lu" sort="Lu, Lu" uniqKey="Lu L" first="Lu" last="Lu">Lu Lu</name>
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<term>Cell Line, Tumor</term>
<term>Crystallography, X-Ray</term>
<term>Drug Design</term>
<term>Enfuvirtide</term>
<term>HIV Envelope Protein gp41 (chemical synthesis)</term>
<term>HIV Envelope Protein gp41 (pharmacology)</term>
<term>HIV Fusion Inhibitors (chemical synthesis)</term>
<term>HIV Fusion Inhibitors (pharmacology)</term>
<term>HIV-1 (chemistry)</term>
<term>HIV-1 (drug effects)</term>
<term>HIV-1 (growth & development)</term>
<term>HIV-1 (metabolism)</term>
<term>Humans</term>
<term>Hydrophobic and Hydrophilic Interactions</term>
<term>Models, Molecular</term>
<term>Neuroglia (drug effects)</term>
<term>Neuroglia (immunology)</term>
<term>Neuroglia (virology)</term>
<term>Peptide Fragments (chemical synthesis)</term>
<term>Peptide Fragments (pharmacology)</term>
<term>Protein Interaction Domains and Motifs</term>
<term>Protein Multimerization</term>
<term>Protein Structure, Secondary</term>
<term>Sequence Alignment</term>
<term>Structure-Activity Relationship</term>
<term>T-Lymphocytes (drug effects)</term>
<term>T-Lymphocytes (immunology)</term>
<term>T-Lymphocytes (virology)</term>
<term>Virus Internalization (drug effects)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Alignement de séquences</term>
<term>Conception de médicament</term>
<term>Cristallographie aux rayons X</term>
<term>Fragments peptidiques (pharmacologie)</term>
<term>Fragments peptidiques (synthèse chimique)</term>
<term>Humains</term>
<term>Inhibiteurs de fusion du VIH (pharmacologie)</term>
<term>Inhibiteurs de fusion du VIH (synthèse chimique)</term>
<term>Interactions hydrophobes et hydrophiles</term>
<term>Lignée cellulaire tumorale</term>
<term>Lymphocytes T ()</term>
<term>Lymphocytes T (immunologie)</term>
<term>Lymphocytes T (virologie)</term>
<term>Modèles moléculaires</term>
<term>Motifs et domaines d'intéraction protéique</term>
<term>Multimérisation de protéines</term>
<term>Névroglie ()</term>
<term>Névroglie (immunologie)</term>
<term>Névroglie (virologie)</term>
<term>Protéine d'enveloppe gp41 du VIH (pharmacologie)</term>
<term>Protéine d'enveloppe gp41 du VIH (synthèse chimique)</term>
<term>Pénétration virale ()</term>
<term>Relation structure-activité</term>
<term>Structure secondaire des protéines</term>
<term>Séquence d'acides aminés</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (croissance et développement)</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (métabolisme)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>HIV Envelope Protein gp41</term>
<term>HIV Fusion Inhibitors</term>
<term>Peptide Fragments</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>HIV Envelope Protein gp41</term>
<term>HIV Fusion Inhibitors</term>
<term>Peptide Fragments</term>
</keywords>
<keywords scheme="MESH" type="chemical" xml:lang="en"><term>Enfuvirtide</term>
</keywords>
<keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>HIV-1</term>
</keywords>
<keywords scheme="MESH" qualifier="croissance et développement" xml:lang="fr"><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>HIV-1</term>
<term>Neuroglia</term>
<term>T-Lymphocytes</term>
<term>Virus Internalization</term>
</keywords>
<keywords scheme="MESH" qualifier="growth & development" xml:lang="en"><term>HIV-1</term>
</keywords>
<keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Lymphocytes T</term>
<term>Névroglie</term>
</keywords>
<keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Neuroglia</term>
<term>T-Lymphocytes</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>HIV-1</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Fragments peptidiques</term>
<term>Inhibiteurs de fusion du VIH</term>
<term>Protéine d'enveloppe gp41 du VIH</term>
</keywords>
<keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Fragments peptidiques</term>
<term>Inhibiteurs de fusion du VIH</term>
<term>Protéine d'enveloppe gp41 du VIH</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Lymphocytes T</term>
<term>Névroglie</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Neuroglia</term>
<term>T-Lymphocytes</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term>
<term>Cell Line, Tumor</term>
<term>Crystallography, X-Ray</term>
<term>Drug Design</term>
<term>Humans</term>
<term>Hydrophobic and Hydrophilic Interactions</term>
<term>Models, Molecular</term>
<term>Protein Interaction Domains and Motifs</term>
<term>Protein Multimerization</term>
<term>Protein Structure, Secondary</term>
<term>Sequence Alignment</term>
<term>Structure-Activity Relationship</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Alignement de séquences</term>
<term>Conception de médicament</term>
<term>Cristallographie aux rayons X</term>
<term>Humains</term>
<term>Interactions hydrophobes et hydrophiles</term>
<term>Lignée cellulaire tumorale</term>
<term>Lymphocytes T</term>
<term>Modèles moléculaires</term>
<term>Motifs et domaines d'intéraction protéique</term>
<term>Multimérisation de protéines</term>
<term>Névroglie</term>
<term>Pénétration virale</term>
<term>Relation structure-activité</term>
<term>Structure secondaire des protéines</term>
<term>Séquence d'acides aminés</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">20 (enfuvirtide) and other peptides derived from the human immunodeficiency virus type 1 (HIV-1) gp41 C-terminal heptad repeat (CHR) region inhibit HIV fusion by binding to the hydrophobic grooves on the N-terminal heptad repeat (NHR) trimer and blocking six-helix-bundle (6-HB) formation. Several strategies focusing on the binding grooves of the NHR trimer have been adopted to increase the antiviral activity of the CHR peptides. Here, we developed a novel and simple strategy to greatly enhance the potency of the existing peptide-based HIV fusion inhibitors. First, we identified a shallow pocket adjacent to the groove in the N-terminal region of NHR trimer as a new drug target, and then we designed several short artificial peptides to fit this target. After the addition of IDL (Ile-Asp-Leu) to the C terminus of CHR peptide WQ or MT-WQ, the conjugated peptides, WQ-IDL and MT-WQ-IDL, showed much more potent activities than WQ and T20, respectively, in inhibiting HIV-1 IIIB infection. WQ-IDL and MT-WQ-IDL were also more effective than WQ in blocking HIV-1 Env-mediated membrane fusion and had higher levels of binding affinity with NHR peptide N46. We solved the crystal structure of the 6-HB formed by MT-WQ-IDL and N46 and found that, besides the N-terminal MT hook tail, the IDL tail anchor of MT-WQ-IDL also binds with the shallow hydrophobic pocket outside the groove of the NHR trimer, resulting in enhanced inhibition of HIV-1 fusion with the target cell. It is expected that this novel approach can be widely used to improve the potency of peptidic fusion inhibitors against other enveloped viruses with class I fusion proteins.</div>
</front>
</TEI>
<affiliations><list><country><li>République populaire de Chine</li>
</country>
<settlement><li>Pékin</li>
</settlement>
</list>
<tree><country name="République populaire de Chine"><noRegion><name sortKey="Su, Shan" sort="Su, Shan" uniqKey="Su S" first="Shan" last="Su">Shan Su</name>
</noRegion>
<name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name>
<name sortKey="Lu, Lu" sort="Lu, Lu" uniqKey="Lu L" first="Lu" last="Lu">Lu Lu</name>
<name sortKey="Ma, Zhenxuan" sort="Ma, Zhenxuan" uniqKey="Ma Z" first="Zhenxuan" last="Ma">Zhenxuan Ma</name>
<name sortKey="Qi, Qianqian" sort="Qi, Qianqian" uniqKey="Qi Q" first="Qianqian" last="Qi">Qianqian Qi</name>
<name sortKey="Wang, Qian" sort="Wang, Qian" uniqKey="Wang Q" first="Qian" last="Wang">Qian Wang</name>
<name sortKey="Xia, Shuai" sort="Xia, Shuai" uniqKey="Xia S" first="Shuai" last="Xia">Shuai Xia</name>
<name sortKey="Ye, Sheng" sort="Ye, Sheng" uniqKey="Ye S" first="Sheng" last="Ye">Sheng Ye</name>
<name sortKey="Yu, Fei" sort="Yu, Fei" uniqKey="Yu F" first="Fei" last="Yu">Fei Yu</name>
<name sortKey="Zhang, Rongguang" sort="Zhang, Rongguang" uniqKey="Zhang R" first="Rongguang" last="Zhang">Rongguang Zhang</name>
<name sortKey="Zhu, Yun" sort="Zhu, Yun" uniqKey="Zhu Y" first="Yun" last="Zhu">Yun Zhu</name>
</country>
</tree>
</affiliations>
</record>

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Creating an Artificial Tail Anchor as a Novel Strategy To Enhance the Potency of Peptide-Based HIV Fusion Inhibitors.

Creating an Artificial Tail Anchor as a Novel Strategy To Enhance the Potency of Peptide-Based HIV Fusion Inhibitors.

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