Nonpeptide Inhibitors of Measles Virus Entry
Identifieur interne : 004059 ( Main/Exploration ); précédent : 004058; suivant : 004060Nonpeptide Inhibitors of Measles Virus Entry
Auteurs : Aiming Sun [Russie] ; Andrew Prussia [Russie] ; Weiqiang Zhan [Russie] ; Ernest E. Murray [Russie] ; Joshua Doyle [Russie] ; Li-Ting Cheng [Russie] ; Jeong-Joong Yoon [Russie] ; Eugene V. Radchenko [Russie] ; Vladimir A. Palyulin [Russie] ; Richard W. Compans [Russie] ; Dennis C. Liotta [Russie] ; Richard K. Plemper [Russie] ; James P. Snyder [Russie, États-Unis]Source :
- Journal of Medicinal Chemistry [ 0022-2623 ] ; 2006.
Abstract
Measles virus (MV) is one of the most infectious pathogens known. Despite the existence of a vaccine, over 500 000 deaths/year result from MV or associated complications. Anti-measles compounds could conceivably reverse these statistics. Previously, we described a homology model of the MV fusion protein trimer and a putative binding site near the head−neck region. The resulting model permitted the identification of two nonpeptidic entry inhibitors. Here, we present the design, synthesis, and bioevaluation of several series of fusion inhibitors and describe their structure-activity relationships (SAR). Five simply substituted anilides show low-μM blockade of the MV, one of which (AS-48) exhibits IC50 = 0.6−3.0 μM across a panel of wild-type MV strains found in the field. Molecular field topology analysis (MFTA), a 2D QSAR approach based on local molecular properties (atomic charges, hydrogen-bonding capacity and local lipophilicity), applied to the anilide series suggests structural modifications to improve potency.
Url:
DOI: 10.1021/jm0602559
Affiliations:
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Chem.</title><idno type="ISSN">0022-2623</idno><idno type="eISSN">1520-4804</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published">2006</date><date type="published">2006</date><biblScope unit="vol">49</biblScope><biblScope unit="issue">17</biblScope><biblScope unit="page" from="5080">5080</biblScope><biblScope unit="page" to="5092">5092</biblScope></imprint><idno type="ISSN">0022-2623</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2623</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Measles virus (MV) is one of the most infectious pathogens known. Despite the existence of a vaccine, over 500 000 deaths/year result from MV or associated complications. Anti-measles compounds could conceivably reverse these statistics. Previously, we described a homology model of the MV fusion protein trimer and a putative binding site near the head−neck region. The resulting model permitted the identification of two nonpeptidic entry inhibitors. Here, we present the design, synthesis, and bioevaluation of several series of fusion inhibitors and describe their structure-activity relationships (SAR). Five simply substituted anilides show low-μM blockade of the MV, one of which (AS-48) exhibits IC50 = 0.6−3.0 μM across a panel of wild-type MV strains found in the field. Molecular field topology analysis (MFTA), a 2D QSAR approach based on local molecular properties (atomic charges, hydrogen-bonding capacity and local lipophilicity), applied to the anilide series suggests structural modifications to improve potency.</div></front></TEI><affiliations><list><country><li>Russie</li><li>États-Unis</li></country><region><li>District fédéral central</li></region><settlement><li>Moscou</li></settlement></list><tree><country name="Russie"><region name="District fédéral central"><name sortKey="Sun, Aiming" sort="Sun, Aiming" uniqKey="Sun A" first="Aiming" last="Sun">Aiming Sun</name></region><name sortKey="Cheng, Li Ting" sort="Cheng, Li Ting" uniqKey="Cheng L" first="Li-Ting" last="Cheng">Li-Ting Cheng</name><name sortKey="Compans, Richard W" sort="Compans, Richard W" uniqKey="Compans R" first="Richard W." last="Compans">Richard W. Compans</name><name sortKey="Doyle, Joshua" sort="Doyle, Joshua" uniqKey="Doyle J" first="Joshua" last="Doyle">Joshua Doyle</name><name sortKey="Liotta, Dennis C" sort="Liotta, Dennis C" uniqKey="Liotta D" first="Dennis C." last="Liotta">Dennis C. Liotta</name><name sortKey="Murray, Ernest E" sort="Murray, Ernest E" uniqKey="Murray E" first="Ernest E." last="Murray">Ernest E. Murray</name><name sortKey="Palyulin, Vladimir A" sort="Palyulin, Vladimir A" uniqKey="Palyulin V" first="Vladimir A." last="Palyulin">Vladimir A. Palyulin</name><name sortKey="Plemper, Richard K" sort="Plemper, Richard K" uniqKey="Plemper R" first="Richard K." last="Plemper">Richard K. Plemper</name><name sortKey="Prussia, Andrew" sort="Prussia, Andrew" uniqKey="Prussia A" first="Andrew" last="Prussia">Andrew Prussia</name><name sortKey="Radchenko, Eugene V" sort="Radchenko, Eugene V" uniqKey="Radchenko E" first="Eugene V." last="Radchenko">Eugene V. Radchenko</name><name sortKey="Snyder, James P" sort="Snyder, James P" uniqKey="Snyder J" first="James P." last="Snyder">James P. Snyder</name><name sortKey="Yoon, Jeong Joong" sort="Yoon, Jeong Joong" uniqKey="Yoon J" first="Jeong-Joong" last="Yoon">Jeong-Joong Yoon</name><name sortKey="Zhan, Weiqiang" sort="Zhan, Weiqiang" uniqKey="Zhan W" first="Weiqiang" last="Zhan">Weiqiang Zhan</name></country><country name="États-Unis"><noRegion><name sortKey="Snyder, James P" sort="Snyder, James P" uniqKey="Snyder J" first="James P." last="Snyder">James P. Snyder</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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