View source for 5cop


==X-ray crystal structure of wild type HIV-1 protease in complex with GRL-097==
<StructureSection load='5cop' size='340' side='right'caption='[[5cop]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5cop]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5COP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5COP FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=53F:(3R,3AS,4S,7AS)-3-HYDROXYHEXAHYDRO-4H-FURO[2,3-B]PYRAN-4-YL+[(2S,3R)-4-{[(4-AMINOPHENYL)SULFONYL](2-METHYLPROPYL)AMINO}-3-HYDROXY-1-(4-METHOXYPHENYL)BUTAN-2-YL]CARBAMATE'>53F</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5cop FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cop OCA], [https://pdbe.org/5cop PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cop RCSB], [https://www.ebi.ac.uk/pdbsum/5cop PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cop ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/G0X8E8_9HIV1 G0X8E8_9HIV1] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
We identified three non-peptidic HIV-1 protease inhibitors (PIs), GRL-015, -085, and -097 containing tetrahydropyrano-tetrahydrofuran (Tp-THF) with a C5 hydroxyl. The three compounds were potent against a wild-type laboratory HIV-1 strain (HIV-1WT) with 50% effective concentrations (EC50s) of 3.0-49 nM and minimal cytotoxicity with 50% cytotoxic concentrations (CC50) for GRL-015, -085, and -097 of 80, &gt;100, and &gt;100 muM, respectively. All the three compounds potently inhibited the replication of highly PI-resistant HIV-1 variants selected with each of the currently available PIs and recombinant clinical HIV-1 isolates obtained from patients harboring multi-drug resistant HIV-1 variants (HIVMDR). Importantly, darunavir (DRV) was &gt;1,000 times less active against a highly DRV-resistant HIV-1 variant (HIV-1DRV R P51), the three compounds remained active to HIV-1DRV R P51 only with 6.8- to 68-fold reduction. Moreover, the emergence of drug resistant HIV-1s against the three compounds was considerably delayed compared to the case of DRV. Especially, HIV-1 variants resistant to GRL-085 and -097 did not emerge even by using two different highly-DRV-resistant HIV-1s as a starting population. In the structural analyses, Tp-THF of GRL-015, -085, and -097 showed strong hydrogen-bond interactions with the backbone atoms of active-site amino acid residues (Asp29 and Asp30) of HIV-1 protease. A strong hydrogen bonding formation between the hydroxyl moiety of Tp-THF and a carbonyl oxygen atom of Gly48 was newly identified. The present findings warrant that the three compounds be further studied as possible therapeutic agents for treating individuals harboring wild-type and/or HIVMDR. IMPORTANCE: Darunavir (DRV) inhibits the replication of most existing multidrug-resistant HIV-1s and has a high genetic barrier. However, the emergence of highly DRV-resistant HIV-1s (HIVDRV R) has recently been reported in vivo and in vitro. Here we identified three novel HIV-1 protease inhibitors (PIs) containing a tetrahydropyrano-tetrahydrofuran (Tp-THF) moiety with a C5 hydroxyl (GRL-015, -085, and -097), which potently suppress the replication of HIVDRV R. Moreover, the emergence of drug resistant HIV-1s against the three compounds was considerably delayed compared to the case of DRV. The C5 hydroxyl formed a strong hydrogen bonding interaction with the carbonyl oxygen atom of Gly48 of protease as examined in the structural analyses. Interestingly, a compound with Tp-THF lacking the hydroxyl moiety substantially decreased the activity against HIVDRV Rs. The three novel compounds should be further developed as potential drugs for treating individuals harboring wild-type and multi-PI-resistant HIV variants as well as HIVDRV R.

The C5-substituted Tetrahydropyrano-tetrahydofuran-derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs Including Darunavir.,Aoki M, Hayashi H, Yedidi RS, Martyr CD, Takamatsu Y, Aoki-Ogata H, Nakamura T, Nakata H, Das D, Yamagata Y, Ghosh AK, Mitsuya H J Virol. 2015 Nov 18. pii: JVI.01829-15. PMID:26581995<ref>PMID:26581995</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5cop" style="background-color:#fffaf0;"></div>

==See Also==
*[[Immunodeficiency virus protease 3D structures|Immunodeficiency virus protease 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human immunodeficiency virus 1]]
[[Category: Large Structures]]
[[Category: Aoki M]]
[[Category: Das D]]
[[Category: Ghosh AK]]
[[Category: Hayashi H]]
[[Category: Mitsuya H]]
[[Category: Yedidi RS]]