5coo - Revision history

OCA at 12:20, 6 March 2024

OCA — Wed, 06 Mar 2024 12:20:50 GMT

←Older revision		Revision as of 12:20, 6 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5coo]] 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=5COO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5COO FirstGlance]. <br>		<table><tr><td colspan='2'>[[5coo]] 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=5COO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5COO FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=52Z:(3R,3AS,4S,7AS)-3-HYDROXYHEXAHYDRO-4H-FURO[2,3-B]PYRAN-4-YL+[(2S,3R)-3-HYDROXY-1-(4-METHOXYPHENYL)-4-{[(4-METHOXYPHENYL)SULFONYL](2-METHYLPROPYL)AMINO}BUTAN-2-YL]CARBAMATE'>52Z</scene></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.8Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=52Z:(3R,3AS,4S,7AS)-3-HYDROXYHEXAHYDRO-4H-FURO[2,3-B]PYRAN-4-YL+[(2S,3R)-3-HYDROXY-1-(4-METHOXYPHENYL)-4-{[(4-METHOXYPHENYL)SULFONYL](2-METHYLPROPYL)AMINO}BUTAN-2-YL]CARBAMATE'>52Z</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=5coo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5coo OCA], [https://pdbe.org/5coo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5coo RCSB], [https://www.ebi.ac.uk/pdbsum/5coo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5coo ProSAT]</span></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=5coo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5coo OCA], [https://pdbe.org/5coo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5coo RCSB], [https://www.ebi.ac.uk/pdbsum/5coo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5coo ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/G0X8E8_9HIV1 G0X8E8_9HIV1]		[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, >100, and >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 >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®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 5coo" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
	*[[Immunodeficiency virus protease 3D structures\|Immunodeficiency virus protease 3D structures]]		*[[Immunodeficiency virus protease 3D structures\|Immunodeficiency virus protease 3D structures]]
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 12:20, 14 June 2023

OCA — Wed, 14 Jun 2023 12:20:31 GMT

←Older revision		Revision as of 12:20, 14 June 2023
Line 3:		Line 3:
	<StructureSection load='5coo' size='340' side='right'caption='[[5coo]], [[Resolution\|resolution]] 1.80Å' scene=''>		<StructureSection load='5coo' size='340' side='right'caption='[[5coo]], [[Resolution\|resolution]] 1.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5coo]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~9hiv1 9hiv1~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5COO OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5COO FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5coo]] 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=5COO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5COO FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=52Z:(3R,3AS,4S,7AS)-3-HYDROXYHEXAHYDRO-4H-FURO[2,3-B]PYRAN-4-YL+[(2S,3R)-3-HYDROXY-1-(4-METHOXYPHENYL)-4-{[(4-METHOXYPHENYL)SULFONYL](2-METHYLPROPYL)AMINO}BUTAN-2-YL]CARBAMATE'>52Z</scene>~~</td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=52Z:(3R,3AS,4S,7AS)-3-HYDROXYHEXAHYDRO-4H-FURO[2,3-B]PYRAN-4-YL+[(2S,3R)-3-HYDROXY-1-(4-METHOXYPHENYL)-4-{[(4-METHOXYPHENYL)SULFONYL](2-METHYLPROPYL)AMINO}BUTAN-2-YL]CARBAMATE'>52Z</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4hla\|4hla]], [[5cok\|5cok]], [[5con\|5con]]</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=5coo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5coo OCA], [https://pdbe.org/5coo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5coo RCSB], [https://www.ebi.ac.uk/pdbsum/5coo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5coo ProSAT]</span></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">pol ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 9HIV1])~~</td></tr>	+
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5coo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5coo OCA], [~~http~~://pdbe.org/5coo PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5coo RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5coo PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5coo ProSAT]</span></td></tr>	+
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/G0X8E8_9HIV1 G0X8E8_9HIV1]
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 25:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human immunodeficiency virus 1]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Aoki, M]]	+	[[Category: Aoki M]]
-	[[Category: Das, D]]	+	[[Category: Das D]]
-	[[Category: Ghosh~~, A K~~]]	+	[[Category: Ghosh AK]]
-	[[Category: Hayashi, H]]	+	[[Category: Hayashi H]]
-	[[Category: Mitsuya, H]]	+	[[Category: Mitsuya H]]
-	[[Category: Yedidi~~, R S]]~~	+	[[Category: Yedidi RS]]
-	~~[[Category: Darunavir]]~~	+
-	~~[[Category: Grl-085]]~~	+
-	~~[[Category: Hiv-1 protease]]~~	+
-	~~[[Category: Hydrolase-hydrolase inhibitor complex]]~~	+
-	~~[[Category: Hydroxyl]]~~	+
-	~~[[Category: Nonpeptidic]]~~	+
-	~~[[Category: O-methoxy]]~~	+
-	~~[[Category: Protease-inhibitor]]~~	+
-	~~[[Category: Tp-thf~~]]	+

OCA at 11:14, 25 December 2019

OCA — Wed, 25 Dec 2019 11:14:58 GMT

←Older revision		Revision as of 11:14, 25 December 2019
Line 1:		Line 1:

	==X-ray crystal structure of wild type HIV-1 protease in complex with GRL-085==		==X-ray crystal structure of wild type HIV-1 protease in complex with GRL-085==
-	<StructureSection load='5coo' size='340' side='right' caption='[[5coo]], [[Resolution\|resolution]] 1.80Å' scene=''>	+	<StructureSection load='5coo' size='340' side='right'caption='[[5coo]], [[Resolution\|resolution]] 1.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5coo]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/9hiv1 9hiv1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5COO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5COO FirstGlance]. <br>		<table><tr><td colspan='2'>[[5coo]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/9hiv1 9hiv1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5COO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5COO FirstGlance]. <br>
Line 18:		Line 18:
	</div>		</div>
	<div class="pdbe-citations 5coo" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5coo" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Immunodeficiency virus protease 3D structures\|Immunodeficiency virus protease 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Aoki, M]]		[[Category: Aoki, M]]
	[[Category: Das, D]]		[[Category: Das, D]]

OCA at 12:28, 6 November 2017

OCA — Mon, 06 Nov 2017 12:28:45 GMT

←Older revision		Revision as of 12:28, 6 November 2017
Line 3:		Line 3:
	<StructureSection load='5coo' size='340' side='right' caption='[[5coo]], [[Resolution\|resolution]] 1.80Å' scene=''>		<StructureSection load='5coo' size='340' side='right' caption='[[5coo]], [[Resolution\|resolution]] 1.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5coo]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5COO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5COO FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5coo]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/9hiv1 9hiv1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5COO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5COO FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=52Z:(3R,3AS,4S,7AS)-3-HYDROXYHEXAHYDRO-4H-FURO[2,3-B]PYRAN-4-YL+[(2S,3R)-3-HYDROXY-1-(4-METHOXYPHENYL)-4-{[(4-METHOXYPHENYL)SULFONYL](2-METHYLPROPYL)AMINO}BUTAN-2-YL]CARBAMATE'>52Z</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=52Z:(3R,3AS,4S,7AS)-3-HYDROXYHEXAHYDRO-4H-FURO[2,3-B]PYRAN-4-YL+[(2S,3R)-3-HYDROXY-1-(4-METHOXYPHENYL)-4-{[(4-METHOXYPHENYL)SULFONYL](2-METHYLPROPYL)AMINO}BUTAN-2-YL]CARBAMATE'>52Z</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4hla\|4hla]], [[5cok\|5cok]], [[5con\|5con]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4hla\|4hla]], [[5cok\|5cok]], [[5con\|5con]]</td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5coo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5coo OCA], [http://pdbe.org/5coo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5coo RCSB], [http://www.ebi.ac.uk/pdbsum/5coo PDBsum]</span></td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">pol ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 9HIV1])</td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5coo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5coo OCA], [http://pdbe.org/5coo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5coo RCSB], [http://www.ebi.ac.uk/pdbsum/5coo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5coo ProSAT]</span></td></tr>
	</table>		</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">

OCA at 10:22, 26 February 2016

OCA — Fri, 26 Feb 2016 10:22:57 GMT

←Older revision		Revision as of 10:22, 26 February 2016
Line 1:		Line 1:
		+
	==X-ray crystal structure of wild type HIV-1 protease in complex with GRL-085==		==X-ray crystal structure of wild type HIV-1 protease in complex with GRL-085==
	<StructureSection load='5coo' size='340' side='right' caption='[[5coo]], [[Resolution\|resolution]] 1.80Å' scene=''>		<StructureSection load='5coo' size='340' side='right' caption='[[5coo]], [[Resolution\|resolution]] 1.80Å' scene=''>

OCA at 20:13, 13 January 2016

OCA — Wed, 13 Jan 2016 20:13:46 GMT

←Older revision		Revision as of 20:13, 13 January 2016
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==X-ray crystal structure of wild type HIV-1 protease in complex with GRL-085==
		+	<StructureSection load='5coo' size='340' side='right' caption='[[5coo]], [[Resolution\|resolution]] 1.80Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5coo]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5COO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5COO FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=52Z:(3R,3AS,4S,7AS)-3-HYDROXYHEXAHYDRO-4H-FURO[2,3-B]PYRAN-4-YL+[(2S,3R)-3-HYDROXY-1-(4-METHOXYPHENYL)-4-{[(4-METHOXYPHENYL)SULFONYL](2-METHYLPROPYL)AMINO}BUTAN-2-YL]CARBAMATE'>52Z</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4hla\|4hla]], [[5cok\|5cok]], [[5con\|5con]]</td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5coo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5coo OCA], [http://pdbe.org/5coo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5coo RCSB], [http://www.ebi.ac.uk/pdbsum/5coo PDBsum]</span></td></tr>
		+	</table>
		+	<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, >100, and >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 >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 ~~entry 5coo is ON HOLD until Paper Publication~~	+	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>

-	~~Authors: Yedidi~~, R.S.~~, Hayashi, H~~., Aoki, M., Das, D~~., Ghosh, A.K., Mitsuya, H.~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description: X-ray crystal structure of wild type HIV-1 protease in complex with GRL-085~~	+	<div class="pdbe-citations 5coo" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Unreleased Structures~~]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Aoki, M]]
		+	[[Category: Das, D]]
		+	[[Category: Ghosh, A K]]
	[[Category: Hayashi, H]]		[[Category: Hayashi, H]]
-	[[Category: Ghosh, A.K]]
-	[[Category: Aoki, M]]
	[[Category: Mitsuya, H]]		[[Category: Mitsuya, H]]
-	[[Category: Yedidi, R.S]]	+	[[Category: Yedidi, R S]]
-	[[Category: ~~Das, D~~]]	+	[[Category: Darunavir]]
		+	[[Category: Grl-085]]
		+	[[Category: Hiv-1 protease]]
		+	[[Category: Hydrolase-hydrolase inhibitor complex]]
		+	[[Category: Hydroxyl]]
		+	[[Category: Nonpeptidic]]
		+	[[Category: O-methoxy]]
		+	[[Category: Protease-inhibitor]]
		+	[[Category: Tp-thf]]

OCA at 10:39, 16 December 2015

OCA — Wed, 16 Dec 2015 10:39:29 GMT

←Older revision		Revision as of 10:39, 16 December 2015
Line 7:		Line 7:
	Description: X-ray crystal structure of wild type HIV-1 protease in complex with GRL-085		Description: X-ray crystal structure of wild type HIV-1 protease in complex with GRL-085
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Ghosh, A.K]]
-	[[Category: Yedidi, R.S]]
-	[[Category: Das, D]]
	[[Category: Hayashi, H]]		[[Category: Hayashi, H]]
		+	[[Category: Ghosh, A.K]]
	[[Category: Aoki, M]]		[[Category: Aoki, M]]
	[[Category: Mitsuya, H]]		[[Category: Mitsuya, H]]
		+	[[Category: Yedidi, R.S]]
		+	[[Category: Das, D]]

OCA at 18:47, 5 August 2015

OCA — Wed, 05 Aug 2015 18:47:01 GMT

←Older revision		Revision as of 18:47, 5 August 2015
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5coo is ON HOLD	+	The entry 5coo is ON HOLD until Paper Publication

	Authors: Yedidi, R.S., Hayashi, H., Aoki, M., Das, D., Ghosh, A.K., Mitsuya, H.		Authors: Yedidi, R.S., Hayashi, H., Aoki, M., Das, D., Ghosh, A.K., Mitsuya, H.

OCA: Protected "5coo" [edit=sysop:move=sysop]

OCA — Wed, 29 Jul 2015 13:39:38 GMT

Protected "5coo" [edit=sysop:move=sysop]

←Older revision

Revision as of 13:39, 29 July 2015

OCA: New page: '''Unreleased structure''' The entry 5coo is ON HOLD Authors: Yedidi, R.S., Hayashi, H., Aoki, M., Das, D., Ghosh, A.K., Mitsuya, H. Description: X-ray crystal structure of wild type H...

OCA — Wed, 29 Jul 2015 13:39:37 GMT

New page: '''Unreleased structure''' The entry 5coo is ON HOLD Authors: Yedidi, R.S., Hayashi, H., Aoki, M., Das, D., Ghosh, A.K., Mitsuya, H. Description: X-ray crystal structure of wild type H...

New page

'''Unreleased structure'''

The entry 5coo is ON HOLD

Authors: Yedidi, R.S., Hayashi, H., Aoki, M., Das, D., Ghosh, A.K., Mitsuya, H.

Description: X-ray crystal structure of wild type HIV-1 protease in complex with GRL-085
[[Category: Unreleased Structures]]
[[Category: Ghosh, A.K]]
[[Category: Yedidi, R.S]]
[[Category: Das, D]]
[[Category: Hayashi, H]]
[[Category: Aoki, M]]
[[Category: Mitsuya, H]]