skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Design of HIV Protease Inhibitors Based on Inorganic Polyhedral Metallacarboranes

Abstract

HIV protease (HIV PR) is a primary target for anti-HIV drug design. We have previously identified and characterized substituted metallacarboranes as a new class of HIV protease inhibitors. In a structure-guided drug design effort, we connected the two cobalt bis(dicarbollide) clusters with a linker to substituted ammonium group and obtained a set of compounds based on a lead formula [H{sub 2}N-(8-(C{sub 2}H{sub 4}O){sub 2}-1,2-C{sub 2}B{sub 9}H{sub 10})(1',2'-C{sub 2}B{sub 9}H{sub 11})-3,3'-Co){sub 2}]Na. We explored inhibition properties of these compounds with various substitutions, determined the HIV PR:inhibitor crystal structure, and computationally explored the conformational space of the linker. Our results prove the capacity of linker-substituted dual-cage cobalt bis(dicarbollides) as lead compounds for design of more potent inhibitors of HIV PR.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;  [1] more »;  [1];  [1] « less
  1. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1006094
Resource Type:
Journal Article
Resource Relation:
Journal Name: J. Med. Chem.; Journal Volume: 52; Journal Issue: (22) ; 11, 2009
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; AIDS VIRUS; CAPACITY; COBALT; CRYSTAL STRUCTURE; DESIGN; LEAD COMPOUNDS; TARGETS

Citation Formats

Rezacova, Pavlina, Pokorna, Jana, Brynda, Ji, Kozisek, Milan, Cigler, Petr, Lesik, Martin, Fanfrlik, Jindrich, Rezac, Jan, Saskova, Klara Grantz, Sieglova, Irena, Plesek, Jaromir, Sicha, Vaclav, Gruner, Bohumir, Oberwinkler, Heike, Sedlacek, Juraj, Krausslich, Hans-Georg, Hobza, Pavel, Kral, Vladimir, Konvalinka, Jan, Heidelberg), ASCR-ICP), and ICT-Czech). Design of HIV Protease Inhibitors Based on Inorganic Polyhedral Metallacarboranes. United States: N. p., 2010. Web. doi:10.1021/jm9011388.
Rezacova, Pavlina, Pokorna, Jana, Brynda, Ji, Kozisek, Milan, Cigler, Petr, Lesik, Martin, Fanfrlik, Jindrich, Rezac, Jan, Saskova, Klara Grantz, Sieglova, Irena, Plesek, Jaromir, Sicha, Vaclav, Gruner, Bohumir, Oberwinkler, Heike, Sedlacek, Juraj, Krausslich, Hans-Georg, Hobza, Pavel, Kral, Vladimir, Konvalinka, Jan, Heidelberg), ASCR-ICP), & ICT-Czech). Design of HIV Protease Inhibitors Based on Inorganic Polyhedral Metallacarboranes. United States. doi:10.1021/jm9011388.
Rezacova, Pavlina, Pokorna, Jana, Brynda, Ji, Kozisek, Milan, Cigler, Petr, Lesik, Martin, Fanfrlik, Jindrich, Rezac, Jan, Saskova, Klara Grantz, Sieglova, Irena, Plesek, Jaromir, Sicha, Vaclav, Gruner, Bohumir, Oberwinkler, Heike, Sedlacek, Juraj, Krausslich, Hans-Georg, Hobza, Pavel, Kral, Vladimir, Konvalinka, Jan, Heidelberg), ASCR-ICP), and ICT-Czech). 2010. "Design of HIV Protease Inhibitors Based on Inorganic Polyhedral Metallacarboranes". United States. doi:10.1021/jm9011388.
@article{osti_1006094,
title = {Design of HIV Protease Inhibitors Based on Inorganic Polyhedral Metallacarboranes},
author = {Rezacova, Pavlina and Pokorna, Jana and Brynda, Ji and Kozisek, Milan and Cigler, Petr and Lesik, Martin and Fanfrlik, Jindrich and Rezac, Jan and Saskova, Klara Grantz and Sieglova, Irena and Plesek, Jaromir and Sicha, Vaclav and Gruner, Bohumir and Oberwinkler, Heike and Sedlacek, Juraj and Krausslich, Hans-Georg and Hobza, Pavel and Kral, Vladimir and Konvalinka, Jan and Heidelberg) and ASCR-ICP) and ICT-Czech)},
abstractNote = {HIV protease (HIV PR) is a primary target for anti-HIV drug design. We have previously identified and characterized substituted metallacarboranes as a new class of HIV protease inhibitors. In a structure-guided drug design effort, we connected the two cobalt bis(dicarbollide) clusters with a linker to substituted ammonium group and obtained a set of compounds based on a lead formula [H{sub 2}N-(8-(C{sub 2}H{sub 4}O){sub 2}-1,2-C{sub 2}B{sub 9}H{sub 10})(1',2'-C{sub 2}B{sub 9}H{sub 11})-3,3'-Co){sub 2}]Na. We explored inhibition properties of these compounds with various substitutions, determined the HIV PR:inhibitor crystal structure, and computationally explored the conformational space of the linker. Our results prove the capacity of linker-substituted dual-cage cobalt bis(dicarbollides) as lead compounds for design of more potent inhibitors of HIV PR.},
doi = {10.1021/jm9011388},
journal = {J. Med. Chem.},
number = (22) ; 11, 2009,
volume = 52,
place = {United States},
year = 2010,
month = 4
}
  • Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps.more » A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 Angstroms resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.« less
  • In our quest for HIV-1 protease inhibitors that are not affected by the V82A resistance mutation, we have synthesized and tested a second generation set of C2-symmetric HIV-1 protease inhibitors that contain a cyclohexane group at P1 and/or P1'. The binding affinity results indicate that these compounds have an improved response to the appearance of the V82A mutation than the parent compound. The X-ray structure of one of these compounds with the V82A HIV-1 PR variant provides the structural rationale for the better resistance profile of these compounds. Moreover, scrutiny of the X-ray structure suggests that the ring of themore » Cha side chain might be in a boat rather than in the chair conformation, a result supported by molecular dynamics simulations.« less
  • Recently, we designed a series of novel HIV-1 protease inhibitors incorporating a stereochemically defined bicyclic fused cyclopentyl (Cp-THF) urethane as the high affinity P2-ligand. Inhibitor 1 with this P2-ligand has shown very impressive potency against multi-drug-resistant clinical isolates. Based upon the 1-bound HIV-1 protease X-ray structure, we have now designed and synthesized a number of meso-bicyclic ligands which can conceivably interact similarly to the Cp-THF ligand. The design of meso-ligands is quite attractive as they do not contain any stereocenters. Inhibitors incorporating urethanes of bicyclic-1,3-dioxolane and bicyclic-1,4-dioxane have shown potent enzyme inhibitory and antiviral activities. Inhibitor 2 (K{sub i} =more » 0.11 nM; IC{sub 50} = 3.8 nM) displayed very potent antiviral activity in this series. While inhibitor 3 showed comparable enzyme inhibitory activity (K{sub i} = 0.18 nM) its antiviral activity (IC{sub 50} = 170 nM) was significantly weaker than inhibitor 2. Inhibitor 2 maintained an antiviral potency against a series of multi-drug resistant clinical isolates comparable to amprenavir. A protein-ligand X-ray structure of 3-bound HIV-1 protease revealed a number of key hydrogen bonding interactions at the S2-subsite. We have created an active model of inhibitor 2 based upon this X-ray structure.« less