In vitro antiviral activity and cross-resistance profile of PL-100, a novel protease inhibitor of human immunodeficiency virus type 1.

Despite the success of highly active antiretroviral therapy, the current emergence and spread of drug-resistant variants of human immunodeficiency virus (HIV) stress the need for new inhibitors with distinct properties. We designed, produced, and screened a library of compounds based on an original l-lysine scaffold for their potentials as HIV type 1 (HIV-1) protease inhibitors (PI). One candidate compound, PL-100, emerged as a specific and noncytotoxic PI that exhibited potent inhibition of HIV-1 protease and viral replication in vitro (K(i), approximately 36 pM, and 50% effective concentration [EC(50)], approximately 16 nM, respectively).

Lysine sulfonamides as novel HIV-protease inhibitors: Nepsilon-acyl aromatic alpha-amino acids.

A series of lysine sulfonamide analogues bearing Nepsilon-acyl aromatic amino acids were synthesized using an efficient synthetic route. Evaluation of these novel protease inhibitors revealed compounds with high potency against wild-type and multiple-protease inhibitor-resistant HIV viruses.

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.