Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The phosphinic acid isosteres of di-, tetra- and hexapeptides containing a hydrophobic amino acid side chains at the P1-P'1 positions are powerful inhibitors of Human Immunodeficiency Virus protease. Ki's ranged from 0.4 nM to 26 microM at pH 6.5 and were lower at pH 4.5. The compounds showed no activity against trypsin, weak activity against renin at pH 6.5, moderate activity against pepsin at pH 2.0 (Ki values in the microM range) and substantial activity against cathepsin D at pH 3.5 (Ki values from 9 to 300 nM).
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PMID:Selective phosphinate transition-state analogue inhibitors of the protease of human immunodeficiency virus. 211 5

The nonapeptide H-Val-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-NH2 containing the retroviral Tyr-Pro cleavage site is a good substrate for the proteinase of human immunodeficiency viruses but it is not readily hydrolyzed by other nonviral proteinases including the structurally related pepsin-like aspartic proteinases. Replacing the Pro by L-pipecolic acid (2-piperidinecarboxylic acid) converted the substrate into an effective inhibitor of HIV-1 and HIV-2 proteinases with IC50 of approximately 1 microM. This compound showed a high degree of selectivity in that it did not inhibit cathepsin D and renin.
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PMID:Substitution of proline with pipecolic acid at the scissile bond converts a peptide substrate of HIV proteinase into a selective inhibitor. 219 May 54

To determine their value as markers of the clinical stage of human immunodeficiency virus (HIV) disease, plasma activities of lysosomal glycosidases were determined in the plasma of 97 HIV-infected patients: molecular forms of cathepsin D were characterized by Western blot to examine the mode of enzyme release. In patients with Centers for Disease Control and Prevention stage II and III of HIV disease, plasma activity of beta-hexosaminidase was significantly increased. In patients with stage III infection, alpha-mannosidase activity was also significantly increased and cathepsin D was elevated and present only in its premature form. Thus, determination of plasma activities of beta-hexosaminidase and alpha-mannosidase in HIV-positive persons may be useful for distinguishing the clinical stage of disease. The elevation of precursors of cathepsin D in patients with stage III HIV disease indicates that secretion of lysosomal enzymes rather than leakage of enzymes from damaged cells is markedly elevated.
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PMID:Elevated levels of activities of beta-hexosaminidase and alpha-mannosidase in human immunodeficiency virus-infected patients. 787 17

Systematic replacement of the P4-P2 subsites of substrate-based human immunodeficiency virus type 1 protease (HIV-1 PR) inhibitors containing cyclohexylalanylalanine hydroxyethylene dipeptide isostere (Cha-psi [H.E.]-Ala) at positions corresponding to the scissile sites of substrates was carried out. The structure-activity relationship revealed that compounds with the combination of hydrophilic P3 and beta-branched hydrophobic P2 amino acids generally showed strong inhibitory activity against HIV-1 PR. In particular, compounds 4 (Boc-Orn-Val-Cha-psi [H.E.]-Ala-NHBun; Bu(n) = n-butyl, Ki = 11 nM) and 6 (Z-Orn-Val-Cha-psi [H.E.]-Ala-NHBun, Ki = 8 nM) exhibited good enzyme selectivity, possessing no significant inhibitory activities toward closely related aspartic proteases, pepsin, cathepsin D, and renin. As a possible model system for (anti-Mo-MSV/MLV complex (Mo-MSV = Moloney murine sarcoma virus; MLV = murine leukemia virus)) activity was investigated. Both compounds were found to inhibit moderately the focus formation of Mo-MSV/MLV complex in NIH3T3 cells (compound 4, IC50 = 1.8 microM; compound 6, IC50 = 1.0 microM).
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PMID:Studies of human immunodeficiency virus type 1 (HIV-1) protease inhibitors. III. Structure-activity relationship of HIV-1 protease inhibitors containing cyclohexylalanylalanine hydroxyethylene dipeptide isostere. 800 98

A series of HIV protease inhibitors containing a novel C2 symmetrical "aminodiol" core structure were prepared from amino acid starting materials. The ability of the aminodiols to inhibit HIV replication in cell culture is comparable to their ability to inhibit the isolated enzyme, a result compatible with good cell membrane penetration by this class of compounds. Optimization of the structure-activity in this series led to aminodiol 9a (Ki = 100 nM; ED50 (HIV-1) = 80 nM) containing P1/P1 benzyl and P2/P2 Boc substituents. Compound 9a is a selective inhibitor of HIV protease versus other aspartyl proteases such as human renin, human cathepsin D, and porcine pepsin. In addition, 9a is equipotent against HIV-1 and HIV-2 in cell culture and demonstrates similar activity in infected T-lymphocytes and PBMCs. After i.v. and oral administration in rats, 9a displayed significant oral bioavailability (ca. 40%) and a promising plasma elimination half-life (4 h).
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PMID:Aminodiol HIV protease inhibitors. 1. Design, synthesis, and preliminary SAR. 802 16

In order to find new effective HIV protease inhibitors, two diterpenes (carnosic acid [1] and carnosol [5]) were isolated from rosemary (Rosmarinus officinalis L.), and rosmanol [2] and semisynthetic derivatives (7-O-methylrosmanol [3], 7-O-ethylrosmanol [4], and 11,12-O,O-dimethylcarnosol [6]) were prepared. The inhibitory activity of all six compounds against HIV-1 protease was tested. The carnosic acid [1] showed the strongest inhibitory effect (IC90 = 0.08 micrograms/ml). The same compound was also assayed against HIV-1 virus replication (IC90 = 0.32 micrograms/ml). The cytotoxic TC90 on H9 lymphocytes was 0.36 micrograms/ml, which is very close to the effective antiviral dose. Additionally, the tested compounds did not inhibit cellular aspartic proteases cathepsin D and pepsin at the concentration range up to 10 micrograms/ml [corrected].
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PMID:Inhibitory effect of carnosic acid on HIV-1 protease in cell-free assays [corrected]. 822 21

The C2-symmetric diester 1 was identified by random screening as a novel inhibitor of HIV-1 proteinase. This led to the preparation of a series of related more potent amides from readily accessible penicillins. Many of the compounds showed potent antiviral activity in HIV-1-infected MT-4 cells and an ability to inhibit syncytia formation in infected C8166 cells, with no evidence of cytotoxicity. The compounds showed no activity against other aspartyl proteinases (renin, pepsin, and cathepsin D). Structure-activity relationships support a symmetrical interaction with the enzyme. Pharmacokinetic evaluation of the ethylamide 3 revealed it was subject to rapid plasma clearance and had low oral bioavailability.
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PMID:A series of penicillin derived C2-symmetric inhibitors of HIV-1 proteinase: synthesis, mode of interaction, and structure-activity relationships. 823 98

CGP 53437 is a peptidomimetic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease containing a hydroxyethylene isostere. The compound inhibited recombinant HIV-1 protease with a Ki of 0.2 nM. The inhibition constant versus human cathepsin D and human cathepsin E was 4 nM. Human pepsin and gastricsin were inhibited with Kis of 8 and 500 nM, respectively, and human renin was inhibited with a Ki of 190 microM. The replication of HIV-1/LAV, HIV-1/Z-84, and HIV-1/pLAI was inhibited with a 90% effective dose of 0.1 microM in acutely infected MT-2 cells. The 50% cytotoxic dose was 100 microM. Similar antiviral activity was observed when the compound was added up to 10 h after infection. At the effective concentration, processing of Gag precursor protein p55 was greatly reduced, confirming an action on the late stage of the virus life cycle, as expected. The efficacy of the inhibitor was also demonstrated by using primary human peripheral blood lymphocytes infected with the HIV-1/LAV strain, low-passage clinical isolates obtained from HIV-1-seropositive individuals (including a zidovudine-resistant strain), and HIV-2/ROD. In these cells, CGP 53437 delayed the onset of HIV replication in a dose-dependent fashion (substantial effects with concentrations of > or = 0.1 microM) as long as the inhibitor was maintained in the culture. CGP 53437 was orally bioavailable in mice. Concentrations in plasma 10-fold in excess of the in vitro antiviral 90% effective dose could be sustained for several hours after oral application of 120 mg/kg. Therefore, CGP 53437 has the potential to be a therapeutically useful anti-HIV agent for the treatment of AIDS.
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PMID:CGP 53437, an orally bioavailable inhibitor of human immunodeficiency virus type 1 protease with potent antiviral activity. 825 28

The FACS-analysis of diseases as different as cancer, autoimmune disorders and chronic (retro)viral infections, including HIV-infection, shows -at least temporarily- a common feature of lymphocyte hyperactivation, characterized by cellular activation markers (HLA-DR, CD26, CD38, CD69, CD2R and/or CD30), as well as by solubilized membrane structures, such as beta-2m, sICAM-I, sIL-2R/sCD25, sCD8, and by some oversecreted immunocyte products (e.g. neopterin, lysozyme and/or cathepsin D). We tested two potential approaches to down-regulate the pathologically elevated CD8+ and HLA-DR+ T cells: (a) In animal model, we tested the sensibility of these, disease inducing and maintaining T cell subsets to in vitro pretreated (cell death preprogrammed) semi-syngeneic and allogeneic donor T cells in tumor-bearing mice. (b) In the first clinical study, we used a novel combination of FDA-approved drugs which inhibits Ca(2+)-influx and concomitantly down-regulates cytosolic cAMP in patient's overstimulated immunocompetent cells. We could achieve a 94.6-100% long-term survival in tumor-bearing mice. In patients, large primary tumors and large metastases shrinked by 80-85% and small metastases disappeared completely. Since in HIV-infected persons, the increased number of HLA-DR+ CD38+T (T8) cells is associated with a fall in CD4-level and with development of AIDS, we are looking for the elimination of these HLA-DR+ targets by our novel technique in two AIDS-simulating (FIV/FeLV and SIV) animal models.
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PMID:Treatment of solid tumors should obligatorily be combined with the in vivo codepletion of tumor-protecting, CD8+/HLA-DR(+)-suppressor T cells by alloreactive donor T cells whose preprogrammed cell death allows a high GvL-effect before GvHD can be established. Results of animal experiments, including more than 6000 mice. 873 48

The HIV protease (or proteinase) enzyme is an essential component of the replicative cycle of HIV, performing the post-transitional processing of the gag and gag-pol gene products into the functional core proteins and viral enzymes. Inhibition of this enzyme leads to production of immature noninfectious viral progeny, and hence prevention of further rounds of infection. Structurally, the enzyme is a homodimer consisting of two identical 99 amino acid chains. HIV protease is a member of the aspartic protease family but is structurally dissimilar to human aspartic proteases such as renin, gastricsin and cathepsin D and E, suggesting the possibility of creating inhibitors with a wide therapeutic index. At least 6 inhibitors of HIV protease are currently in clinical development: saquinavir, indinavir, ritonavir, nelfinavir (AG-1343), KNI-272 and VX-478, the first four of which have shown antiretroviral activity and acceptable tolerability in initial phase I/II clinical trials. Resistance or reduced sensitivity to the leading protease inhibitors has been reported in vivo and appears to be associated with loss of therapeutic effect. However, resistance patterns appear to be distinct. Treatment for 1 year with indinavir has been reported to lead to selection of virus in 4 patients, which was cross-resistant to all other leading protease inhibitors. On the other hand, a larger series of clinical isolates from patients receiving saquinavir alone or in combination with zidovudine for up to 3 years did not lead to virus cross-resistant to either indinavir or ritonavir. This suggests that care should be exercised in designing the sequence of protease usage. Additionally, differing resistance patterns may be used to select combinations of protease inhibitors in future trials. Data from studies combining protease inhibitors with nucleoside analogues suggest value in terms of larger and more prolonged virological and immunological marker responses than are observed with single agent therapy, and this is likely to be the primary role for protease inhibitors; both in initial combinations for patients commencing therapy and as add-in therapies for patients previously treated with antiretrovirals. However, in vitro and animal pharmacokinetic studies also give evidence of the possibility of combining protease inhibitors, potentially leading to improved bioavailability, antiviral synergy and delay in emergence of viral resistance.
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PMID:Current knowledge and future prospects for the use of HIV protease inhibitors. 886 42


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