Inhibition of human immunodeficiency virus-1 protease by a C2-symmetric phosphinate. Synthesis and crystallographic analysis (original) (raw)
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Design and synthesis of inhibitors for the HIV-1 protease
1994
A variety of phosphonamidate-containing peptides were synthesised as potential inhibitors of the HIV-1 protease. These transition state analogues were designed using known sequences from HIV-1 protease substrates and incorporated a unique Phe-Pro scissile bond mimic in an attempt to achieve selectivity over the mammalian aspartic proteases. Such compounds were found to be moderate inhibitors of the HiV-1 protease possessing iCgo values in the 1-100 pM range, both in in vitro and in vivo assays. However, the phosphonamidate methyl ester analogues showed a marked ability to enter ceils and this feature was highlighted in the 1:1 ratio of in vivo/ in vitro iCso values (generally for peptidic inhibitors, this ratio is 10-10000 fold higher, indicating poor cell uptake properties). Optimisation of the methyl ester analogues was attempted by alteration of the binding residues flanking either side of the phosphonamidate moiety. However, such alterations had only a small effect on inhibitor ...
Journal of Virology, 2014
Insertions in the protease (PR) region of human immunodeficiency virus (HIV) represent an interesting mechanism of antiviral resistance against HIV PR inhibitors (PIs). Here, we demonstrate the improved ability of a phosphonate-containing experimental HIV PI, GS-8374, relative to that of other PIs, to effectively inhibit patient-derived recombinant HIV strains bearing PR insertions and numerous other mutations. We correlate enzyme inhibition with the catalytic activities of corresponding recombinant PRs in vitro and provide a biochemical and structural analysis of the PR-inhibitor complex.
Antiviral chemistry & chemotherapy, 1998
A series of human immunodeficiency virus (HIV) protease inhibitors, which are analogues of N-[2(R)-hydroxy-1(S)- indanyl]-5(S)-[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-(R) - [[4-(carboxymethoxy)phenyl]methyl]hexanamide (L-694,746), a metabolite of the anti-HIV agent L-689,502, were synthesized. In these compounds, the acetic group linked to the para position of the P1' phenyl in the reference inhibitor was replaced either by the bioisosteric phosphonomethoxy group and its diisopropyl/dibenzyl derivatives, or the 1H-tetrazol-5-yl-methoxy group and its 1-benzyl derivative. In enzyme assays, phosphonomethoxy and tetrazolmethoxy analogues proved to be potent inhibitors of the HIV-1 protease, with IC50 values as low as 0.04 nM. When tested for anti-HIV-1 activity in cell-based assays, most of the new derivatives proved active, with benzyl derivatives being more active than their highly polar, unsubstituted counterparts. The dibenzylphosphonomethoxy analogue was the most...
Antimicrobial Agents and Chemotherapy, 2011
ABSTRACTGS-8374 is a novel bis-tetrahydrofuran HIV-1 protease (PR) inhibitor (PI) with a unique diethylphosphonate moiety. It was selected from a series of analogs containing various di(alkyl)phosphonate substitutions connected via a linker to theparaposition of a P-1 phenyl ring. GS-8374 inhibits HIV-1 PR with high potency (Ki= 8.1 pM) and with no known effect on host proteases. Kinetic and thermodynamic analysis of GS-8374 binding to PR demonstrated an extremely slow off rate for the inhibitor and favorable contributions of both the enthalpic and entropic components to the total free binding energy. GS-8374 showed potent antiretroviral activity in T-cell lines, primary CD4+T cells (50% effective concentration [EC50] = 3.4 to 11.5 nM), and macrophages (EC50= 25.5 nM) and exhibited low cytotoxicity in multiple human cell types. The antiviral potency of GS-8374 was only moderately affected by human serum protein binding, and its combination with multiple approved antiretrovirals show...
Design of new inhibitors of HIV-1 aspartic protease
We present an approach for designing new inhibitors (I) of HIV-1 aspartic protease (PR) based on calculation of relative binding energies, taking into account contributions from all species involved in the complexation equilibrium (I + PR * I:PR), as well as their solvation. This allows a rational design of new structures with predicted enhanced inhibitory potency. We have also analysed the role in binding affinity of the central non-scissile bond (X1-X2) as well as of flanking amino acid residues Pn of inhibitor structures (P3-P2-Pl -Xl -X2-P l'-P2'-P3'). 0301-0104/96/$15.00 0 1996 Elsevier Science B.V. All rights reserved SSDI 0301-0104(95)00363-O
Structure Based Design of Inhibitors of Aspartic Protease of HIV-1
Letters in Drug Design & Discovery, 2005
The aspartic protease of HIV-1 represents a valid therapeutic target of antiviral agents suitable for the treatment of AIDS. We have designed peptidomimetic inhibitors for this enzyme with a hydroxyethylenediamine core, based on a molecular modeling approach that predicts the effectiveness of the designed compounds in terms of computed enzyme-inhibitor complexation Gibbs free energies. This structurebased molecular design was then combined with a synthetic strategy that couples stereochemical control with full flexibility in the choice of the central core side chains and of the flanking residues. A series of peptidomimetic inhibitors was thus assembled from readily available amino acids and carboxylic acids and -Phe-ψ[CH 2 -(r/s)CHOH]-Phe-cores. The IC 50 values for these compounds ranged from 3 nM to 80 µM , allowing a QSAR analysis and identification of factors that determine the inhibition potency of the compounds. Predicted ADME-related properties of the inhibitor candidates span a range of pharmacokinetics profiles, which allows selection of a potent and bioavailable lead compound for further development.
INHIBITORS OF HIV-1 PROTEASE: A Major Success of Structure-Assisted Drug Design 1
Annual Review of Biophysics and Biomolecular Structure, 1998
Retroviral protease (PR) from the human immunodeficiency virus type 1 (HIV-1) was identified over a decade ago as a potential target for structure-based drug design. This effort was very successful. Four drugs are already approved, and others are undergoing clinical trials. The techniques utilized in this remarkable example of structure-assisted drug design included crystallography, NMR, computational studies, and advanced chemical synthesis. The development of these drugs is discussed in detail. Other approaches to designing HIV-1 PR inhibitors, based on the concepts of symmetry and on the replacement of a water molecule that had been found tetrahedrally coordinated between the enzyme and the inhibitors, are also discussed. The emergence of drug-induced mutations of HIV-1 PR leads to rapid loss of potency of the existing drugs and to the need to continue the development process. The structural basis of drug resistance and the ways of overcoming this phenomenon are mentioned.