Peptidic protease inhibitors

Further, Wasserman and coworkers developed a direct acylation of stabilized phosphonium ylides by carboxylic acids in presence of the EDCI/DMAP (way c). This last method allows the introduction of a-aminoacid structures into the resulting P-oxo phosphorus ylides [19-25],opening the way to the total synthesis of depsipeptide elastase inhibitors [22,24] or cyclic peptidic protease inhibitor EurystatinA [20]. 

Doyon L, Tremblay S, Bourgon L, Wardrop E, et al. 2005. Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptide protease inhibitor tipranavir. Antiviral Res. 68 27-35. 

While a few very potent non-peptide protease inhibitors (Pis) have been isolated from plants many plant protease inhibitor proteins (PIPs) have evolved to have protease interaction Kj values in the nanomolar and picomolar range. These extraordinary affinities derive from the matching of the PI protein amino sequence about the scissile peptide bond (Pl-Pl ) and evolution of adjacent sequences to fit and interact appropriately within the target protease active site [1, 120, 121]. The structure and function of the different classes of PI proteins from plants are succinctly but comprehensively reviewed below. 

In the continuous quest for new generations of HIV inhibitors, Pfizer identified the thiosubstituted pyrones as a new class of non-peptidic protease inhibitors [97]. 

Type III Topographical mimetics Structure-based design Non-peptide protease inhibitors... 

Nelflnavir mesylate is a protease inhibitor that inhibits human immunodeficiency virus (HIV) protease, the enzyme required to form functional proteins in HIV-infected cells. It is indicated in the treatment or HIV infection in combination with other antiretroviral agents. Nelflnavir is a non-peptidic protease inhibitor that is active against both HIV-1 and HIV-2 and is formulated as the mesylate salt of a basic amine. The mean IC95 for HTV-1 in various in vitro assays is 59 nM. Like most drugs in this class, nelfinavir was a product of rational drug design. 

Atazanavir Atazanavir is a peptide protease inhibitor that is active against both HlV-1 and HlV-2. Absorption is increased by food and it is recommended that the drug be administered with a meal. Absorption may be pH dependent, because proton pump inhibitors substantially reduce drug concentration after oral dosing. Like indinavir, atazanavir frequently causes unconjugated hyperbilirubinemia. The drug may be less likely than other HIV protease inhibitors to cause lipodystrophy. 

Scheme 4 Cyclic urea based on non-peptidic protease inhibitors reaching clinical trials [13]...

A number of peptidic protease inhibitors are currently used in clinical practice. Although these inhibitors represent a major advance in HIV chemotherapy, adverse side effects and viral resistance is a cause of constant concern. A further limitation of current protease inhibitors is their complexity and difficult synthetic pathway with high cost of production, hi order to overcome all these difficulties, it is desirable to identify new inhibitors of simpler structure. Up to now, only one non-peptide compound (Tipranavir, 7) has been approved for HIV treatment. Some reached chnical trials but could not be developed further, signifying the urgent need for development of new inhibitors. 

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