In vitro anti-HIV-1 activity of HIV protease inhibitor KNI-272 in resting and activated cells: implications for its combined use with AZT or ddI

Chokekijchai, Sudhichai; Shirasaka, Takuma; Weinstein, John N.; Mitsuya, Hiroaki

doi:10.1016/0166-3542(95)00036-l

Cited by 11 publications

(5 citation statements)

References 27 publications

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“…The high degree of potency of this compound was attributed to conformational preorganization as the overall conformation of KNI-272 in the HIV-1 PR complex is remarkably similar to that observed in single crystal structures of KNI-272 in the free form [30,31]. However, the pharmacokinetics of KNI-272 are characterized by limited bioavailability, limited distribution and rapid elimination [32][33][34]. Moreover, HIV-1 develops in vitro a high level of resistance to KNI-272.…”

Section: Statinementioning

confidence: 52%

Approaches to the Design of Effective HIV-1 Protease Inhibitors

Lebon¹,

Ledecq

2000

CMC

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Recently, western countries have recorded a decrease in the death rate imputed to AIDS. This success has been largely attributed to the presence on the market of chemotherapies that inhibit the infectivity of the predominant causative agent, the HIV-1 virus, by targeting essential viral enzymes. One of these is the protease (HIV-1 PR) whose activity is a prerequisite for viral replication. Two main sites have been identified as potential targets for the inhibition of HIV-1 PR, the active site and the interface, the latter being largely responsible for the stabilization of the enzyme dimeric structure. The compounds that have reached clinical application so far target the active site of HIV-1 PR. These molecules act as transition state analogues and result from modifications of the peptidic scaffold into peptidomimetics. In order to improve their bioavailability, systematic biological screening and de novo design have been used to suggest new non-peptide inhibitors combining both antiviral potency and favorable pharmacokinetic properties. In parallel, compounds targeting other potential sites of inhibition have been tested. Peptides and peptidomimetics based on the terminal sequence of the enzyme, a site which is proposed to be less susceptible to mutations, have been shown to lead to HIV-1 PR inactivation. Cupric ion was described to bind a sequence on the protease surface, which includes cysteine and histidine residues, leading to the inhibition of the enzyme. In the future, these non-active site inhibitors could provide an alternative in anti-HIV drug combination strategies.

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Section: Statinementioning

confidence: 52%

Approaches to the Design of Effective HIV-1 Protease Inhibitors

Lebon¹,

Ledecq

2000

CMC

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“…This observation has been utilized to design a novel class of cyclic urea type inhibitors3a whose specificity derives from their ability to mimic and replace W301, as observed in the crystalline state 3a and in solution 3b. W301 and several other water molecules are observed at the protease/drug interface in the crystal structure of the protease complexed with KNI-272, Figure , a highly potent inhibitor, currently in clinical trials . This observation suggests that, in addition to W301, these water molecules may have an important role in the formation of the protease/KNI-272 complex.…”

Section: Introductionmentioning

confidence: 94%

“…3b W301 and several other water molecules are observed at the protease/drug interface in the crystal structure of the protease complexed with KNI-272, Figure 1, 4 a highly potent inhibitor, currently in clinical trials. 5 This observation suggests that, in addition to W301, these water molecules may have an important role in the formation of the protease/KNI-272 complex. Herein we report NMR studies 4 showing the locations of the six ordered water molecules.…”

Section: Introductionmentioning

confidence: 99%

Bound Water Molecules at the Interface between the HIV-1 Protease and a Potent Inhibitor, KNI-272, Determined by NMR

et al. 1996

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KNI-272 is a peptidomimetic transition state analog inhibitor, having very high specificity and binding affinity for the HIV-1 protease. In order to understand the interactions that enhance drug binding to the protease, we recorded 2D water/NOESY and water/ROESY spectra to identify water molecules that bind tightly to the protease/KNI-272 complex. Well-ordered water molecules are observed at the protease/inhibitor interface in the crystal structure of the complex that have short interproton distances to the Ile50/150, Ala28/128, and Asp29/129 amide protons. The cross peaks between these protein protons and water protons, observed in water/NOESY and water/ROESY spectra, provide strong evidence that these water molecules are present in the solution structure of the complex. Analysis of measured NOE and ROE cross relaxation rates indicates that, in solution, these water molecules have long residence times, at least 1 ns and possibly greater than 7 ns. The presence of long-lived hydration water molecules at the protein/inhibitor interface suggests that interactions involving these water molecules contribute to the potency of the inhibitor. Hence, consideration of the potential role of hydration water molecules in stabilizing protein/inhibitor structures could contribute to improved drug design and to a better understanding of the mechanisms of drug resistance.

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“…KNI-272 is highly selective and nontoxic, with favorable therapeutic indices and pharmacokinetic behavior in animals (Kageyama et al, 1993). It is currently undergoing phase 1 clinical trials (Chokeijichai et al, 1995). A 2.0 Å X-ray crystal structure of the protease/KNI-272 complex has been solved (Baldwin et al, 1995), providing a structural basis for understanding the potency of this novel inhibitor.…”

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confidence: 99%

Solution NMR Evidence That the HIV-1 Protease Catalytic Aspartyl Groups Have Different Ionization States in the Complex Formed with the Asymmetric Drug KNI-272

et al. 1996

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In order to improve the design of HIV-1 protease inhibitors, it is essential to understand how they interact with active site residues, particularly the catalytic Asp25 and Asp125 residues. KNI-272 is a promising, potent HIV-1 protease inhibitor (K(i) approximately 5 pM), currently undergoing phase 1 clinical trials. Because KNI-272 is asymmetric, the complex it forms with the homodimeric HIV-1 protease also lacks symmetry, and the two protease monomers can have distinct NMR spectra. Monomer specific signal assignments were obtained for amino acid residues in the drug binding site as well as for six of the eight Asp residues in the protease/KNI-272 complex. Using these assignments, the ionization states of the Asp carboxyl groups were determined from measurements of (a) the pD dependence of the chemical shifts of the Asp carboxyl carbons and (b) the H/D isotope effect upon the Asp carboxyl carbon chemical shifts. The results of these measurements indicate that the carboxyl of Asp25 is protonated while that of Asp125 is not protonated. These findings provide not only the first experimental evidence regarding the distinct protonation states of Asp25/125 in HIV-1 protease/drug complexes, but also shed light on interactions responsible for inhibitor binding that should form the basis for improved drug designs.

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In vitro anti-HIV-1 activity of HIV protease inhibitor KNI-272 in resting and activated cells: implications for its combined use with AZT or ddI

Cited by 11 publications

References 27 publications

Approaches to the Design of Effective HIV-1 Protease Inhibitors

Approaches to the Design of Effective HIV-1 Protease Inhibitors

Bound Water Molecules at the Interface between the HIV-1 Protease and a Potent Inhibitor, KNI-272, Determined by NMR

Solution NMR Evidence That the HIV-1 Protease Catalytic Aspartyl Groups Have Different Ionization States in the Complex Formed with the Asymmetric Drug KNI-272

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