Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.16 (HIV-1 protease)
 2,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have evaluated a possible role for human immunodeficiency virus type 1 protease during early steps of replication. For these studies, a specific inhibitor of human immunodeficiency virus protease, Ro31-8959, was used. Synthesis of viral cDNA, its integration into cellular DNA, and its transcription were determined during a one-step, acute infection of MT-4 cells. No consistent difference in any of these parameters was noted between control-infected cultures and those treated with protease inhibitor. However, no infectious progeny virus was produced in treated cultures, and thus spread of infection was severely restricted. Our results do not support an essential activity of viral protease in early steps of replication but are in line with its established role in gag and gag-pol processing and in maturation to infectious progeny virus.
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PMID:Progression of early steps of human immunodeficiency virus type 1 replication in the presence of an inhibitor of viral protease. 137 15

Starting from highly potent HIV-1 protease pepstatine analog inhibitors, we have tried to find the minimum consensus sequence which is necessary to conserve anti-protease potency and antiviral activity. We describe here some statine based tripeptides which exhibit high affinity for the protease and are able to inhibit the reproductive cycle of HIV-1 in MT-4-infected cells.
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PMID:Statine based tripeptides as potent inhibitors of HIV-1 replication. 144 28

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

A series of novel difluoroketones with low molecular weight (less than 600 m.u.) and which are potent inhibitors of the HIV-1 protease (IC50 = 1.0 to 21 nM) were synthesized. These compounds also exhibited antiviral activity by inhibition of the cytopathic effect of HIV-1(3)B in MT-4 cells in vitro.
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PMID:Potent HIV-1 protease inhibitors with antiviral activities in vitro. 202 63

A series of novel pseudo-symmetrical and unsymmetrical inhibitors based on the backbone modification of a peptidomimetic were synthesized and found to be highly potent inhibitors of the HIV-1 protease (IC50 = 2.9 to < 0.5 nM). These compounds also possess good antiviral activity in vitro as measured by inhibition of the cytopathic effect of HIV-1(3B) in MT-4 lymphocytes. Importantly, some of these compounds also have good oral bioavailabilities in rats (F = 30.6% to 100%). One of these compounds 4C, also has good oral bioavailability in beagle dogs and cynomolgus monkeys.
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PMID:Potent inhibitors of the HIV-1 protease with good oral bioavailabilities. 777 82

A series of novel, pseudo-symmetrical difluoroketones which are highly potent inhibitors of the HIV-1 protease (IC50 = 1.55-0.02 nM) were synthesized. These compounds also possess good antiviral activity by inhibition of the cytopathic effect of HIV-13B in MT-4 cells in vitro.
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PMID:Pseudo-symmetrical difluoroketones. Highly potent and specific inhibitors of HIV-1 protease. 835 89

Halogenated gomisin J (a derivative of lignan compound), represented by the bromine derivative 1506 [(6R, 7S, S-biar)-4,9-dibromo-3,10-dihydroxy-1,2,11,12-tetramethoxy-6, 7-dimethyl-5,6,7,8- tetrahydrodibenzo[a,c]cyclo-octene], was found to be a potent inhibitor of the cytopathic effects of human immunodeficiency virus type 1 (HIV-1) on MT-4 human T cells (50% effective dose, 0.1 to 0.5 microM). Gomisin J derivatives were active in preventing p24 production from acutely HIV-1-infected H9 cells. The selective indices (toxic dose/effective dose) of these compounds were as high as > 300 in some systems. 1506 was active against 3'-azido-3'-deoxythymidine-resistant HIV-1 and acted synergistically with AZT and 2',3'-ddC. 1506 inhibited HIV-1 reverse transcriptase (RT) in vitro but not HIV-1 protease. From the time-of-addition experiment, 1506 was found to inhibit the early phase of the HIV life cycle. A 1506-resistant HIV mutant was selected and shown to possess a mutation within the RT-coding region (at position 188 [Tyr to Leu]). The mutant RT expressed in Escherichia coli was resistant to 1506 in the in vitro RT assay. Some of the HIV strains resistant to other nonnucleoside HIV-1 RT inhibitors were also resistant to 1506. Comparison of various gomisin J derivatives with gomisin J showed that iodine, bromine, and chlorine in the fourth and ninth positions increased RT inhibitory activity as well as cytoprotective activity.
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PMID:Anti-human immunodeficiency virus (HIV) activities of halogenated gomisin J derivatives, new nonnucleoside inhibitors of HIV type 1 reverse transcriptase. 854 Jul 6

The human immunodeficiency virus type 1 (HIV-1) protease catalyses the specific cleavage of the virion structural polyproteins p55gag and p160gag-pol and is, therefore, essential for viral maturation. We have previously reported a series of low molecular weight non-peptidic enol-based compounds that inhibit the HIV-1 protease activity in a competitive fashion (Vaillancourt et al., Bioorg. Med. Chem., 2 (1994) 343-355). Here we demonstrate that VS-215 and VS-261, two of these non-peptidic inhibitors, impair viral polyprotein maturation and exhibit antiviral activity in infected MT4 cells. The ID50 for these two compounds ranged between 24 and 50 microM whereas their TD50 ranged between 60 and 200 microM depending on the cell lines used. The calculated therapeutic index of these two inhibitors both had values of 2.5 even though they were shown to be non cytotoxic at their ID50. Their calculated permeability index ranged between 0.09 and 0.79 suggesting that these enol-based inhibitors efficiently reach the site of protease activity. These results provide new information on the therapeutic potential of this new class of protease inhibitors and emphasize the usefulness of enol chemistry in the development of anti-HIV-1 protease inhibitors.
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PMID:Antiviral properties of simple difunctionalized enols targeted to the HIV-1 protease. 854 Jul 44

The design, synthesis, and molecular modeling studies of a novel series of azacyclic ureas, which are inhibitors of human immunodeficiency virus type 1 (HIV-1) protease that incorporate different ligands for the S1', S2, and S2' substrate-binding sites of HIV-1 protease are described. The synthesis of this series is highly flexible in the sense that the P1', P2, and P2' residues of the inhibitors can be changed independently. Molecular modeling studies on the phenyl ring of the P2 and P2' ligand suggested incorporation of hydrogen-bonding donor/acceptor groups at the 3' and 4-positions of the phenyl ring should increase binding potency. This led to the discovery of compound 7f (A-98881), which possesses high potency in the HIV-1 protease inhibition assay and the in vitro MT-4 cell culture assay (Ki = approximately 5 pM and EC50 = 0.002 microM). This compares well with the symmetrical cyclic urea 1 pioneered at DuPont Merck.
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PMID:A novel, picomolar inhibitor of human immunodeficiency virus type 1 protease. 855 7

A series of omega-undecanoic amides of lup-20(29)-en-28-oic acid derivatives were synthesized and evaluated for activity in CEM 4 and MT-4 cell cultures against human immunodeficiency virus type 1 (HIV-1) strain IIIB/LAI. The potent HIV inhibitors which emerged, compounds 5a, 16a, and 17b, were all derivatives of betulinic acid (3beta-hydroxylup-20(29)-en-28-oic acid). No activity was found against HIV-2 strain ROD. Compound 5a showed no inhibition of HIV-1 reverse transcriptase activity with poly(C).oligo(dG) as template/primer, nor did it inhibit HIV-1 protease. Additional mechanistic studies revealed that this class of compounds interfere with HIV-1 entry in the cells at a postbinding step.
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PMID:Betulinic acid derivatives: a new class of human immunodeficiency virus type 1 specific inhibitors with a new mode of action. 867 41


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