Triple Hyp→Pro replacement in integramide A, a peptaib inhibitor of HIV‐1 integrase: Effect on conformation and bioactivity
Identifieur interne : 002507 ( Main/Exploration ); précédent : 002506; suivant : 002508Triple Hyp→Pro replacement in integramide A, a peptaib inhibitor of HIV‐1 integrase: Effect on conformation and bioactivity
Auteurs : Marta De Zotti [Italie] ; Wim De Borggraeve [Belgique] ; Bernard Kaptein [Pays-Bas] ; Quirinus B. Broxterman [Pays-Bas] ; Sheo B. Singh [États-Unis] ; Peter J. Felock [États-Unis] ; Daria J. Hazuda [États-Unis] ; Fernando Formaggio [Italie] ; Claudio Toniolo [Italie]Source :
- Peptide Science [ 0006-3525 ] ; 2011.
English descriptors
- Teeft :
- Amphipathic features, Analog, Bioactivity, Bioactivity measurements, Biol chem, Biopolymers, Bruker avance spectrometer, Cdcl3, Cdcl3 solution, Chem, Chem lett, Chemical shifts, Circular dichroism, Conformation, Conformational preferences, Corresponding spectra, Decrements cycles, Diastereomeric, Diastereomeric hexadecapeptides, Diastereomeric integramide, Distance geometry, Dmso, Energy minimization, Ftir, Ftir absorption, Ftir absorption spectra, Helical, Helical conformation, Helical structure, Helix, Hexadecapeptides, Host cell, Infrared absorption, Inhibitor, Integramide, Integrase, Interproton distance restraints, Magn, Magn reson, Merck research laboratories, Natural compound, Natural integramide, Noesy, Noesy spectra, Noesy spectrum, Peptaib inhibitor, Peptide, Peptide concentration, Peptide science, Proc natl acad, Proton, Relaxation delay, Reson, Room temperature, Selective excitation, Spectral width, Strand transfer reactions, Synthetic step, Tocsy spectra, Toniolo, Triple replacement, Wiley periodicals, Zotti.
Abstract
AIDS is produced by HIV‐induced infections. HIV integrase is an important enzyme as it is critical for the integration of the HIV genome into that of the host cell. This complex process is exclusively carried out by a viral enzyme not found in the host cell. Therefore, this protein represents a safe target for the development of single or combined anti‐HIV therapy. Integramide A is a 16‐mer long, effective peptaib inhibitor of HIV‐1 integrase. We have previously described a versatile synthetic strategy in solution to afford this natural compound and its diastereomer at positions 14 and 15. We also found that both peptides display a significant inhibitory activity. Here, we present our data on the synthesis in solution, in‐depth conformational analysis, and biological activity against HIV‐integrase of the analogs of the two above mentioned peptides in which all of the three (2S,4R)‐Hyp residues at positions 2, 9, and 13 are replaced by L‐Pro. This study definitely confirms that the mixed α‐/310‐ helical conformation of natural integramide A plays a key role in its mechanism of inhibition. Moreover, our data provide evidence that the amphipathic character of this helical structure is not required for the activity of integramide A against HIV‐1 integrase. These observations will hopefully help us to further clarify the precise mechanism of inhibition of this interesting peptaib and to identify shorter peptide sequences active against HIV‐1 integrase. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 49–59, 2011.
Url:
DOI: 10.1002/bip.21461
Affiliations:
- Belgique, Italie, Pays-Bas, États-Unis
- New Jersey, Pennsylvanie, Province du Brabant flamand
- Heverlee, Louvain
- Katholieke Universiteit Leuven
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Box 18, 6160 MD Geleen</wicri:regionArea><wicri:noRegion>6160 MD Geleen</wicri:noRegion></affiliation></author><author><name sortKey="Broxterman, Quirinus B" sort="Broxterman, Quirinus B" uniqKey="Broxterman Q" first="Quirinus B." last="Broxterman">Quirinus B. Broxterman</name><affiliation wicri:level="1"><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>DSM, Innovative Synthesis BV, P.O. Box 18, 6160 MD Geleen</wicri:regionArea><wicri:noRegion>6160 MD Geleen</wicri:noRegion></affiliation></author><author><name sortKey="Singh, Sheo B" sort="Singh, Sheo B" uniqKey="Singh S" first="Sheo B." last="Singh">Sheo B. Singh</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Merck Research Laboratories, West Point</wicri:cityArea></affiliation></author><author><name sortKey="Felock, Peter J" sort="Felock, Peter J" uniqKey="Felock P" first="Peter J." last="Felock">Peter J. 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HIV integrase is an important enzyme as it is critical for the integration of the HIV genome into that of the host cell. This complex process is exclusively carried out by a viral enzyme not found in the host cell. Therefore, this protein represents a safe target for the development of single or combined anti‐HIV therapy. Integramide A is a 16‐mer long, effective peptaib inhibitor of HIV‐1 integrase. We have previously described a versatile synthetic strategy in solution to afford this natural compound and its diastereomer at positions 14 and 15. We also found that both peptides display a significant inhibitory activity. Here, we present our data on the synthesis in solution, in‐depth conformational analysis, and biological activity against HIV‐integrase of the analogs of the two above mentioned peptides in which all of the three (2S,4R)‐Hyp residues at positions 2, 9, and 13 are replaced by L‐Pro. This study definitely confirms that the mixed α‐/310‐ helical conformation of natural integramide A plays a key role in its mechanism of inhibition. Moreover, our data provide evidence that the amphipathic character of this helical structure is not required for the activity of integramide A against HIV‐1 integrase. These observations will hopefully help us to further clarify the precise mechanism of inhibition of this interesting peptaib and to identify shorter peptide sequences active against HIV‐1 integrase. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 49–59, 2011.</div></front></TEI><affiliations><list><country><li>Belgique</li><li>Italie</li><li>Pays-Bas</li><li>États-Unis</li></country><region><li>New Jersey</li><li>Pennsylvanie</li><li>Province du Brabant flamand</li></region><settlement><li>Heverlee</li><li>Louvain</li></settlement><orgName><li>Katholieke Universiteit Leuven</li></orgName></list><tree><country name="Italie"><noRegion><name sortKey="De Zotti, Marta" sort="De Zotti, Marta" uniqKey="De Zotti M" first="Marta" last="De Zotti">Marta De Zotti</name></noRegion><name sortKey="Formaggio, Fernando" sort="Formaggio, Fernando" uniqKey="Formaggio F" first="Fernando" last="Formaggio">Fernando Formaggio</name><name sortKey="Toniolo, Claudio" sort="Toniolo, Claudio" uniqKey="Toniolo C" first="Claudio" last="Toniolo">Claudio Toniolo</name><name sortKey="Toniolo, Claudio" sort="Toniolo, Claudio" uniqKey="Toniolo C" first="Claudio" last="Toniolo">Claudio Toniolo</name><name sortKey="Toniolo, Claudio" sort="Toniolo, Claudio" uniqKey="Toniolo C" first="Claudio" last="Toniolo">Claudio Toniolo</name></country><country name="Belgique"><region name="Province du Brabant flamand"><name sortKey="De Borggraeve, Wim" sort="De Borggraeve, Wim" uniqKey="De Borggraeve W" first="Wim" last="De Borggraeve">Wim De Borggraeve</name></region></country><country name="Pays-Bas"><noRegion><name sortKey="Kaptein, Bernard" sort="Kaptein, Bernard" uniqKey="Kaptein B" first="Bernard" last="Kaptein">Bernard Kaptein</name></noRegion><name sortKey="Broxterman, Quirinus B" sort="Broxterman, Quirinus B" uniqKey="Broxterman Q" first="Quirinus B." last="Broxterman">Quirinus B. Broxterman</name></country><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Singh, Sheo B" sort="Singh, Sheo B" uniqKey="Singh S" first="Sheo B." last="Singh">Sheo B. Singh</name></region><name sortKey="Felock, Peter J" sort="Felock, Peter J" uniqKey="Felock P" first="Peter J." last="Felock">Peter J. Felock</name><name sortKey="Hazuda, Daria J" sort="Hazuda, Daria J" uniqKey="Hazuda D" first="Daria J." last="Hazuda">Daria J. Hazuda</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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