Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthesis of analogues of AcSerLeuAsn[Phe-HEA-Pro]IleValOMe (1, JG-365; where HEA stands for the hydroxyethylamine unit 2), a tight-binding inhibitor of HIVP, are reported. Systematic modification of the P3 and P3' regions of the inhibitors has led to smaller HIVP inhibitors that inhibit viral replication in HIV-infected and SIV-infected cell cultures. Six aliphatic and/or aromatic derivatives were prepared by replacing residues in the P3 regions of BocLeuAsn[Phe-HEA-Pro]IleValOMe. Aromatic side chains at P3 gave better inhibitors than aliphatic side chains. The better inhibitors in this series contained a beta-naphthylalanine or a biphenyl unit at P3. A second series of HIVP inhibitors were obtained by converting the P3 group into acyl groups. CbzAsn[Phe-HEA-Pro]IlePheOMe and Qua-Asn-[Phe-HEA-Pro]-Ile-Phe-OMe (where Qua = quinolin-2-ylcarbonyl) are potent HIVP inhibitors with Ki values equal to 1.0 and 0.1 nM, respectively. The inhibition constants were determined by using the continuous fluorometric assay developed by Toth and Marshall. The activities of the protease inhibitors for inhibition of SIV replication were determined in vitro using CEM x 174 cells. Inhibition of HIV infection was determined essentially as reported by Pauwels and co-workers. The anti-HIV assay was carried out in culture using CEM cells (a CD4+ lymphocyte line) infected with virus strain HTLV-IIIb with a multiplicity of infection of 0.1. Several analogues inhibited the cytopathic effect at concentrations of 0.1-0.8 microgram/mL. These results establish that good inhibitors of HIV protease that inhibit viral replication in infected lymphocytes in in vitro cell assays can be obtained from JG-365 when the AcSerLeu unit is replaced by aromatic acyl derivatives.
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PMID:New hydroxyethylamine HIV protease inhibitors that suppress viral replication. 143 92

A series of HIV-1 protease inhibitors containing a novel hydroxyethyl secondary amine transition state isostere has been synthesized. The compounds exhibit a strong preference for the (R) stereochemistry at the transition state hydroxyl group. Molecular modeling studies with the prototype compound 11 have provided important insights into the structural requirements for good inhibitor-active site binding interaction. N-Terminal extension of 11 into the P2-P3 region led to the discovery of 19, the most potent enzyme inhibitor in the series (IC50 = 5.4 nM). 19 was shown to have potent antiviral activity in cultured MT-4 human T-lymphoid cells. Comparison of analogs of 19 with analogs of 1 (Ro31-8959) demonstrates that considerably different structure-activity relationships exist between these two subclasses of hydroxyethylamine HIV-protease inhibitors.
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PMID:A series of potent HIV-1 protease inhibitors containing a hydroxyethyl secondary amine transition state isostere: synthesis, enzyme inhibition, and antiviral activity. 163 54

Comparative molecular field analysis (CoMFA), a three-dimensional, quantitative structure-activity relationship (QSAR) paradigm, was used to examine the correlations between the calculated physicochemical properties and the in vitro activities of a series of human immunodeficiency virus (HIV-1) protease inhibitors. The training set consisted of 59 molecules from five structurally-diverse transition-state isostere classes: hydroxyethylamine, statine, norstatine, keto amide, and dihydroxyethylene. The availability of X-ray crystallographic data for at least one representative from each class bound to the protease provided information regarding not only the active conformation of each ligand but also, via superimposition of protease backbones, the relative positions of each ligand with respect to one another in the active site of the enzyme. Once aligned, these molecules served as templates on which additional congeners were field-fit minimized. Additional alignment rules were derived from minimizations of the ligands in the active site of the semirigid protease. The predictive ability of each resultant model was evaluated using a test set comprised of molecules containing a novel transition-state isostere: hydroxyethylurea. Crystallographic studies (Getman, D.P.; et al. J. Med. Chem. 1993, 36, 288-291) indicated an unexpected binding mode for this series of compounds which precluded the use of the field-fit minimization alignment technique. The test set molecules were, therefore, subjected to a limited systematic search in conjunction with active-site minimization. The conformer of each molecule expressing the lowest interaction energy with the active site was included in the test set. Field-fit minimization of neutral molecules to crystal ligands and active-site minimizations of protonated ligands yielded predictive correlations for HIV-1 protease inhibitors. The use of crystallographic data in the determination of alignment rules and field-fit minimization as a molecular alignment tool in the absence of direct experimental data regarding binding modes is strongly supported by these results.
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PMID:Three-dimensional QSAR of human immunodeficiency virus (I) protease inhibitors. 1. A CoMFA study employing experimentally-determined alignment rules. 827 96

We present the application of free energy perturbation theory/molecular dynamics to predict the consequence of replacing each of the seven peptide bonds in the potent HIV protease inhibitor JG365: ACE (acetyl)-Ser-Leu-Asn-HEA (hydroxyethylamine analog of Phe-Pro)-Ile-Val-NME (N-methyl) by ethylene or fluoroethylene isosteres. Replacing two of these bonds may well lead to significantly tighter binding; replacing two others is predicted to significantly diminish the binding affinity. Also, for three of the peptide bonds fluoroethylene replacements could lead to increased binding of free energies of the inhibitors. Our results should be considered as predictive since there are, as yet, no experimental results on such peptide replacements as enzyme inhibitors.
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PMID:Peptide mimetics as enzyme inhibitors: use of free energy perturbation calculations to evaluate isosteric replacement for amide bonds in a potent HIV protease inhibitor. 837 26

A novel series of hydroxyethylamine-based inhibitors of HIV protease which contain a substituted pipecolinic amide were developed. After preliminary screening, a representative of this series, compound BILA 2185 BS, demonstrated an IC50 value of 3.3 nM in the enzymatic assay and an EC50 value of 2.0 nM in cell culture. The plasma profile and bioavailability values for BILA 2185 BS in the rat will be presented. The analyte was isolated from rat plasma using a liquid-liquid extraction procedure. The analytical technique used utilizes a high performance liquid chromatography system with photodiode array detector. The range of the standard curve was from 10 to 5000 nM. Recovery values averaged 72.4 +/- 8.6% (mean +/- S.D.). The limit of detection for BILA 2185 BS was 6-12 nM.
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PMID:Determination of the HIV protease inhibitor BILA 2185 BS in rat plasma by liquid-liquid extraction and high performance liquid chromatography photodiode array detector. 883 77

HIV-1 and HIV-2 proteinases (PR) are responsible for the processing of viral polyproteins, a step that is crucial for the formation of infectious virus particles. PR represents one of the most important targets for antiviral chemotherapy. Inhibitors of HIV-1 PR usually exhibit a 10- to 100-fold weaker affinity for HIV-2 PR. In order to design subnanomolar inhibitors for both HIV-1 and HIV-2 PRs, we prepared a series of compounds varying in the type of scissile bond replacement as well as in the P1, P1', and P2' side chains. While inhibitors containing reduced amide, hydroxyethylamine and statine isosteres had Ki values in the range of 10(-10)-10(-9) M against HIV-1 PR; their activities against HIV-2 PR were several orders of magnitude lower. Glutamic acid was identified to be the optimal P2' residue for both PRs. HIV-2 PR was shown to be more sensitive to P2' Glu-->Gln replacement. Using this data set we were able to design and prepare hydroxyethylene isostere containing inhibitors that were equipotent against both PRs.
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PMID:Potency comparison of peptidomimetic inhibitors against HIV-1 and HIV-2 proteinases: design of equipotent lead compounds. 914 53

The catELISA technique was modified and standardized for measuring HIV-1 aspartyl protease activity and evaluating the potency of synthetic peptide inhibitors. This immuno-quantified solid phase assay combines the use of an immobilized C-terminal biotinylated peptide as substrate, a crude enzyme preparation, and a highly specific antiserum elicited against the C-terminal product of the enzyme reaction. A standard curve of this C-terminal product was constructed to determine the enzyme activity. This assay, which requires less enzyme and substrate, is more sensitive than the conventional HPLC method. The amounts of C-terminal peptide produced in solution as determined from ELISA and HPLC standard curves were comparable. Analogues of peptidomimetics designed in our laboratory were assayed for their potency to inhibit the enzyme. One of them, H4, which is a hydroxyethylamine isostere of the Phe-Pro peptide bond, was a powerful inhibitor.
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PMID:Development and standardization of an immuno-quantified solid phase assay for HIV-1 aspartyl protease activity and its application to the evaluation of inhibitors. 914 28

The 2-isopropyl thiazolyl group is a highly optimized P3 ligand for C2 symmetry-based HIV protease inhibitors, as exemplified in the drug ritonavir. Here we report that incorporation of this P3 ligand into a piperazine hydroxyethylamine series also yielded novel, highly potent inhibitors. In tissue culture assays, the presence of human serum was less deleterious to the activity of these inhibitors than to that of ritonavir. Furthermore, potent activity against ritonavir resistant HIV was observed.
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PMID:Potent piperazine hydroxyethylamine HIV protease inhibitors containing novel P3 ligands. 993 66

A set of conformations was shown to be characteristic of the free-state spatial structure of substrate-like inhibitor JG-365 for aspartic protease from HIV-1. Among them, the lowest-energy conformations have a folded form of the peptide backbone. The inhibitor has a noncleavable hydroxyethylamine group with an additional chiral center in its structure. Our calculations showed that only the S-isomer of the inhibitor displays conformational characteristics that practically coincide with those of the native substrate for HIV-1 protease. One of the calculated conformations with a completely extended main chain and a relative energy of 9.5 kcal/mol very closely mimics the experimentally observed structure of the inhibitor in the enzyme-inhibitor complex. The realization of this structure is unlikely for a free inhibitor, because it has only a small number of interresidual noncovalent interactions in the extended conformation; these are presumably compensated for by intermolecular interactions at the active site of the enzyme.
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PMID:[Mechanism of action of aspartic proteases. III. Conformational characteristics of HIV-1 protease inhibitor JG-365]. 1050 29

Starting from palinavir (1), our lead HIV protease inhibitor, we have discovered a new series of truncated analogues in which the P(3)-P(2) quinaldic-valine portion of 1 was replaced by 2', 6'-dimethylphenoxyacetyl. With EC(50)'s in the 1-2 nM range, some of these compounds are among the most potent inhibitors of HIV replication in vitro, reported to date. One of the most promising members in this series (compound 27, BILA 2185 BS) exhibited a favorable overall pharmacokinetic profile, with 61% apparent oral bioavailability in rat. X-ray crystal structures and molecular modeling were used to rationalize the high potency resulting from incorporation of this structurally simple, achiral ligand into the P(3)-P(2) position of hydroxyethylamine-based HIV protease inhibitors.
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PMID:2',6'-Dimethylphenoxyacetyl: a new achiral high affinity P(3)-P(2) ligand for peptidomimetic-based HIV protease inhibitors. 1073 42


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