Design of HIV-1 Protease Inhibitors Active on Multidrug-Resistant Virus

Surleraux, Dominique; Kock, Herman A. De; Verschueren, Wim; Pille, Geert; Maes, Louis; Peeters, Anik; Vendeville, Sandrine; Meyer, Sandra De; Azijn, Hilde; Pauwels, Rudi; Béthune, Marie‐Pierre de; King, Nancy M. P.; Prabu-Jeyabalan, M.; Schiffer, Celia A.; Wigerinck, Piet

doi:10.1021/jm049454n

Cited by 71 publications

(56 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…b 50% effective concentration against wild-type HIV-1 viral activity (44,45). c affinity constant for the binding of the drug to wild-type HIV-1 protease, measured by surface plasmon resonance (36).…”

Section: Tablementioning

confidence: 99%

A Potent HIV Protease Inhibitor, Darunavir, Does Not Inhibit ZMPSTE24 or Lead to an Accumulation of Farnesyl-prelamin A in Cells

Coffinier¹,

Hudon

Lee³

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

HIV protease inhibitors (HIV-PIs) are key components of highly active antiretroviral therapy, but they have been associated with adverse side effects, including partial lipodystrophy and metabolic syndrome. We recently demonstrated that a commonly used HIV-PI, lopinavir, inhibits ZMPSTE24, thereby blocking lamin A biogenesis and leading to an accumulation of prelamin A. ZMPSTE24 deficiency in humans causes an accumulation of prelamin A and leads to lipodystrophy and other disease phenotypes. Thus, an accumulation of prelamin A in the setting of HIV-PIs represents a plausible mechanism for some drug side effects. Here we show, with metabolic labeling studies, that lopinavir leads to the accumulation of the farnesylated form of prelamin A. We also tested whether a new and chemically distinct HIV-PI, darunavir, inhibits ZMPSTE24. We found that darunavir does not inhibit the biochemical activity of ZMP-STE24, nor does it lead to an accumulation of farnesyl-prelamin A in cells. This property of darunavir is potentially attractive. However, all HIV-PIs, including darunavir, are generally administered with ritonavir, an HIV-PI that is used to block the metabolism of other HIV-PIs. Ritonavir, like lopinavir, inhibits ZMP-STE24 and leads to an accumulation of prelamin A.HIV protease inhibitors (HIV-PIs) 3 are designed to inhibit the HIV aspartyl protease, which is required for generating viral core proteins (1). HIV-PIs have become essential elements of modern antiretroviral regimens, but they have been associated with significant side effects, including partial lipodystrophy and metabolic syndrome (2-4). Similar disease phenotypes have been observed in association with missense mutations in LMNA (the gene for lamins A and C) (5, 6) and with genetic defects associated with defective conversion of prelamin A to mature lamin A (7-9).In 2003, Caron et al. (10) reported that a pair of HIV-PIs, indinavir and nelfinavir, appeared to lead to the accumulation of small amounts of prelamin A in a preadipocyte cell line. This finding was intriguing, but the biochemical mechanism was obscure. Potentially, this finding could have been due to the inhibition of any of four different enzymatic steps in prelamin A metabolism. The biogenesis of mature lamin A from prelamin A involves 1) farnesylation of a C-terminal cysteine by protein farnesyltransferase; 2) the removal of the last three amino acids of prelamin A (a redundant enzymatic activity of Ras converting enzyme 1 (RCE1) and ZMPSTE24); 3) the methylation of a newly exposed farnesylcysteine by isoprenylcysteine carboxyl methyltransferase (ICMT); and 4) the removal of the last 15 residues of the protein, including the farnesylcysteine methyl ester, by ZMPSTE24 (11). Steps 2-4 are utterly dependent on the first post-translational processing step, protein farnesylation.Recently, our laboratories showed that several HIV-PIs, but notably lopinavir, lead to substantial prelamin A accumulation in cultured cells at therapeutically relevant concentrations, and we went on to identify the ...

show abstract

Section: Tablementioning

confidence: 99%

A Potent HIV Protease Inhibitor, Darunavir, Does Not Inhibit ZMPSTE24 or Lead to an Accumulation of Farnesyl-prelamin A in Cells

Coffinier¹,

Hudon

Lee³

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Moreover, their clinical use is compromised by high production cost, various side effects, and rapid development of resistant viral strains (4). Therefore, there is a continuing need for the design of new PIs with an emphasis on broad specificity against PI-resistant HIV mutants (5,6).…”

mentioning

confidence: 99%

From nonpeptide toward noncarbon protease inhibitors: Metallacarboranes as specific and potent inhibitors of HIV protease

Cígler

Kožíšek

Řezáčová

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

283

273

View full text Add to dashboard Cite

HIV protease (PR) represents a prime target for rational drug design, and protease inhibitors (PI) are powerful antiviral drugs. Most of the current PIs are pseudopeptide compounds with limited bioavailability and stability, and their use is compromised by high costs, side effects, and development of resistant strains. In our search for novel PI structures, we have identified a group of inorganic compounds, icosahedral metallacarboranes, as candidates for a novel class of nonpeptidic PIs. Here, we report the potent, specific, and selective competitive inhibition of HIV PR by substituted metallacarboranes. The most active compound, sodium hydrogen butylimino bis-8,8-[5-(3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide)]di-ate, exhibited a Ki value of 2.2 nM and a submicromolar EC50 in antiviral tests, showed no toxicity in tissue culture, weakly inhibited human cathepsin D and pepsin, and was inactive against trypsin, papain, and amylase. The structure of the parent cobalt bis(1,2-dicarbollide) in complex with HIV PR was determined at 2.15 Å resolution by protein crystallography and represents the first carborane-protein complex structure determined. It shows the following mode of PR inhibition: two molecules of the parent compound bind to the hydrophobic pockets in the flap-proximal region of the S3 and S3 subsites of PR. We suggest, therefore, that these compounds block flap closure in addition to filling the corresponding binding pockets as conventional PIs. This type of binding and inhibition, chemical and biological stability, low toxicity, and the possibility to introduce various modifications make boron clusters attractive pharmacophores for potent and specific enzyme inhibition. rational drug design ͉ aspartic proteases ͉ carboranes ͉ x-ray structure analysis ͉ virostatics

show abstract

“…Darunavir (previously known as TMC114) (21,28,49,50), recently approved by the FDA, is extremely potent against wild-type HIV as well as a large panel of PI-resistant clinical isolates and shows a high genetic barrier to the development of antiretroviral resistance (9,48). It was suggested that the major structural features of the compound responsible for these favorable properties are a picomolar binding affinity to the wild-type PR binding site, the ability to form numerous backboneto-backbone hydrogen bonds with the PR substrate binding cleft, and the ability to adopt a conformation that fits within the "substrate envelope" of the active site (5,28).…”

mentioning

confidence: 99%

Molecular Characterization of Clinical Isolates of Human Immunodeficiency Virus Resistant to the Protease Inhibitor Darunavir

Šašková

Kožíšek

Řezáčová

et al. 2009

J Virol

View full text Add to dashboard Cite

Darunavir is the most recently approved human immunodeficiency virus (HIV) protease (PR) inhibitor (PI)and is active against many HIV type 1 PR variants resistant to earlier-generation PIs. Darunavir shows a high genetic barrier to resistance development, and virus strains with lower sensitivity to darunavir have a higher number of PI resistance-associated mutations than viruses resistant to other PIs. In this work, we have enzymologically and structurally characterized a number of highly mutated clinically derived PRs with high levels of phenotypic resistance to darunavir. With 18 to 21 amino acid residue changes, the PR variants studied in this work are the most highly mutated HIV PR species ever studied by means of enzyme kinetics and X-ray crystallography. The recombinant proteins showed major defects in substrate binding, while the substrate turnover was less affected. Remarkably, the overall catalytic efficiency of the recombinant PRs (5% that of the wild-type enzyme) is still sufficient to support polyprotein processing and particle maturation in the corresponding viruses. The X-ray structures of drug-resistant PRs complexed with darunavir suggest that the impaired inhibitor binding could be explained by change in the PR-inhibitor hydrogen bond pattern in the P2 binding pocket due to a substantial shift of the aminophenyl moiety of the inhibitor. Recombinant virus phenotypic characterization, enzyme kinetics, and X-ray structural analysis thus help to explain darunavir resistance development in HIV-positive patients.

show abstract

Design of HIV-1 Protease Inhibitors Active on Multidrug-Resistant Virus

Cited by 71 publications

References 34 publications

A Potent HIV Protease Inhibitor, Darunavir, Does Not Inhibit ZMPSTE24 or Lead to an Accumulation of Farnesyl-prelamin A in Cells

A Potent HIV Protease Inhibitor, Darunavir, Does Not Inhibit ZMPSTE24 or Lead to an Accumulation of Farnesyl-prelamin A in Cells

From nonpeptide toward noncarbon protease inhibitors: Metallacarboranes as specific and potent inhibitors of HIV protease

Molecular Characterization of Clinical Isolates of Human Immunodeficiency Virus Resistant to the Protease Inhibitor Darunavir

Contact Info

Product

Resources

About