Pepstatin, hydroxy

Renin inhibitors have been found among naturally occurring phospholipids and synthetic phosphatidylethanolamine derivatives. Pepstatin (5.131), isolated from Streptomyces strains, is a pentapeptide with an acylated N-terminus and the unusual 4-amino-3-hydroxy-6-methylheptanoic acid (AHMH) residues. It is a general protease... 

According to Rich, new protease inhibitors were produced by replacing statine in pepstatin derivatives with (3S,4S)-4,8-diamino-3-hydroxyoctanecarboxylic acid (DAHOA) 85 a 189a) or 4-amino-3-hydroxy-5-phenylpentanecarboxylic acid (AHPPA) 85b 189b-c>. 

Die in Pepstatin, einem Proteaseinhibitor, vorkommende nicht naturliche Aminosaure Statin (3S, 45-4-Amino-3-hydroxy-6-methyl-heptansaure) wurde zur Beantwortung ki-netischer und biologischer Fragestellungen hergestellt172. Der Schliisselsehritt der Statin-Synthese ist die Bis-[2-methyl-propyl]-aluminiumhydrid-Reduktion des BOC-L-Leu-cin-methylester zum entsprechenden Aldehyd mit Bis-[2-methyl-propyl]-aluminiumhy-drid ... 

Two different approaches to ( —)-statine (831), an unusual amino acid component of pepstatine, both employ 793c as their starting point. In the first synthesis (Scheme 120) [183], reduction of 793c with sodium borohydride produces a mixture of two isomeric 5-hydroxy-pyrrolidinones, from which the pure cis product 824 crystallizes in 85% yield. Conversion of bisacetate 825 to thioether 826 followed by removal of the acetate and silylation of the resulting alcohol affords 827. Radical cyclization of 827 produces a 3 2 mixture of isomers 828. Desilylation and debenzylation gives 829 as a single diastereomer. The Boc-protected intermediate 830 intersects with a known synthesis of ( —)-statine (831). 

Statine (Sta), (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, an unusual amino acid occurring as a building block, e.g., in pepstatin [D. H. Richetal.,J. Org. Chem. 1978, 43, 3624]. 

Inhibition of these enzymes is achieved with various diazoacetylamino acid esters, which apparently react with carboxyl groups on the active site, and with pepstatin. The latter is isolated from various Streptomycetes as a peptide mixture with the general formula (R isovaleric or n-caproic acid AHMHA 4-amino-3-hydroxy-6-methyl heptanoic acid) ... 

Figure 6. Structure of pepstatin. The subsites are designated with the assumption that the side chain of the central 4-amino-3-hydroxy-6 methylheptanoic acid residue binds at the Sj subsite of pepsin. Cleavage probabilities are listed under each amino acid residue. Favorable (+) and neutral ( ) probabilities are indicated.

Pepstatin is a strong competitive inhibitor of pepsin which is produced by various strains of actinomycetes (14). The structure (Fig.6) contains an unusual amino acid 4-amino-3-hydroxy-6-methyl-heptanoic acid (statine). Tang has proposed that the statine residue of pepstatin resembles the transition state for pepsin hydrolysis of peptide bonds (15, see also Chapter 12 in this volume). If this is so and the central statine residue binds at the catalytic site with its side chain in the Si subsite, then we note (Fig.6) that the interactions at all the other subsites are favorable or neutral. The P subsites are listed with the assumption that central residue bridges two subsites (Si and SJ). 

Pepstatin is a strong inhibitor for all acid proteases. It does not inhibit other groups of proteases, such as the neutral and alkaline proteases (1), The unusual potency of pepstatin toward acid proteases is indicated by its which was reported by Kunimoto et al. (2) to be about 1 x 10-IOM for porcine pepsin. Although its chemical structure has been shown (3) to be a hexapeptide which contains two residues of an unusual amino acid, 4-amino-3-hydroxy-6-methylhepatanoic acid (statine), the mode of inhibition by pepstatin is unknown. 

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