Lysine derivatives as potent HIV protease inhibitors. Discovery, synthesis and structure-activity relationship studies.

A screening assay program on HIV-protease was carried out on more than fifty commercially available N-protected amino acids and has revealed that those with a long side chain such as lysine, ornithine and arginine exhibited significant inhibition of HIV protease enzyme. The presence of an Fmoc group was found to be essential to obtain micromolar inhibitors and the addition of an alkyl group at the Nalpha-position resulted in the discovery of the lead compound 11 displaying a 5 nM inhibition constant. Although this new inhibitor series is not categorized among those mimicking the substrate with a non-hydrolyzable transition-state isoster, it was found very specific to inhibit HIV protease enzyme in comparison to the mammalian aspartyl proteases pepsin, renin and cathepsin. Furthermore, these inhibitors did not show any cytotoxicity at a concentration below 75 microM.

Lysine sulfonamides as novel HIV-protease inhibitors: Nepsilon-disubstituted ureas.

A series of lysine sulfonamide analogues bearing a Nepsilon-benzylic ureas was synthesized using both solution-phase and solid-phase approaches. A novel synthetic route of Nalpha-(alkyl)-Nalpha-(sulfonamides)lysinol using alpha-amino-caprolactam was developed. Evaluation of these novel protease inhibitors revealed compounds with high potency against wild-type HIV virus.

Lysine sulfonamides as novel HIV-protease inhibitors: optimization of the Nepsilon-acyl-phenyl spacer.

A series of Nalpha-isobutyl-Nalpha-arylsulfonamido-(Nepsilon acyl) lysine and lysinol derivatives were prepared and evaluated as inhibitors of HIV protease and wild type virus. A simple original synthesis was devised to form Nalpha-(arylsulfonamide)-Nalpha-isobutyl lysine, which could be easily acylated with carboxylic acids at the Nepsilon position. A two-atom spacer was found to be optimal between this acyl group and a phenyl yielding compounds of sub-nanomolar potency on purified enzyme.

1,2,5,6-tetra-O-benzyl-D-mannitol derivatives as novel HIV protease inhibitors.

The synthesis and structure-activity relationships of HIV protease inhibitors derived from carbohydrate alditols are discussed. We disclose a new series of 1,2,5,6-tetra-O-alkyl-D-mannitol exhibiting sub-micromolar activity against HIV-protease. This series of inhibitors are non-nitrogen containing HIV-protease inhibitors and they are readily prepared in a few chemical steps from inexpensive commercially available starting materials.

Is antisense an appropriate nomenclature or design for oligodeoxynucleotides aimed at the inhibition of HIV-1 replication?

We have evaluated the specificity and the variation in activity against human immunodeficiency virus (HIV) infection of antisense oligodeoxynucleotides (ODNs) with regard to factors such as dose-response range, number and choice of experimental controls, backbone modifications of the ODNs, type of cell infection, length of assays, and delivery approach. The highest level of inhibition was achieved in our long-term assay with MOLT-3 cells acutely infected with HIV-1 (IIIB) and treated with free phosphorothioate-modified ODNs (PS-ODNs). The highest level of specificity was observed in our short-term assay with MOLT-3 cells acutely infected with HIV-1 (IIIB) and treated with free PS-ODNs. The highest potency (IC50 level) was observed in our short-term chronic-infection model with (DLS)-delivered ODNs in which the DLS delivery improved the ODN activity up to 106 times compared to the activity of free ODNs. Thus, the near blocking of HIV replication obtained when using PS-ODNs appears because of the addition of extracellular and/or membrane effects. The higher efficacy of PS-ODNs compared to unmodified ODNs, when both are delivered with the DLS system, was demonstrated solely in our short-term assay with MOLT-3 cells. Important variations in the level of sequence specificity were observed and depended on the type of control used and the type of cell assay employed. It seems that all 3 groups of control-tested, random, sense sequence, and non-antisense T30177 ODNs might have distinct activity and, consequently, different modes of action in inhibiting HIV replication. Our data buttress the notion that the contribution of the sequence-specific mediated mode of action is minor compared to the other mechanisms involved in ODN antiviral activity.

Silver(I) oxide mediated highly selective monotosylation of symmetrical diols. Application to the synthesis of polysubstituted cyclic ethers.

[reaction: see text] The reaction of symmetrical diols and oligo(ethylene glycol)s with a stoichiometric amount of p-toluenesulfonyl chloride in the presence of silver(I) oxide and a catalytic amount of potassium iodide led selectively to the monotosylate derivatives in high yields. Polysubstituted cyclic ethers were obtained readily upon treatment of the corresponding diols with an excess of silver oxide. The high selectivity was explained on the basis of the difference in acidity between the two hydroxy groups, which undergo an intramolecular hydrogen bonding.

Targeting HIV-1 integrase.

Human immunodeficiency virus Type 1 (HIV-1) integrase is an essential enzyme for the obligatory integration of the viral DNA into the infected cell chromosome. As no cellular homologue of HIV integrase has been identified, this unique HIV-1 enzyme is an attractive target for the development of new therapeutics. Treatment of HIV-1 infection and AIDS currently consists of the use of combinations of HIV-1 inhibitors directed against reverse transcriptase (RT) and protease. However, their numerous side effects and the rapid emergence of drug-resistant variants limit greatly their use in many AIDS patients. In principle, inhibitors of the HIV-1 integrase should be relatively non-toxic and provide additional benefits for AIDS chemotherapy. There have been many major advances in our understanding of the molecular mechanism of the integration reaction, although some critical aspects remain obscure. Several classes of compounds have been screened and further scrutinised for their inhibitory properties against the HIV integrase; however, there are currently no useful inhibitors available clinically for the treatment of AIDS patients. This review describes the current knowledge of the biological functions of the HIV-1 integrase and reports the major classes of integrase inhibitors identified to date.