Design and Synthesis of Depeptidized Macrocyclic Inhibitors of Hepatitis C NS3-4A Protease Using Structure-Based Drug Design

Abstract

Hepatitis C virus (HCV) NS3, when bound to NS-4A cofactor, facilitates development of mature virons by catalyzing cleavage of a polyprotein to form functional and structural proteins of HCV. The enzyme has a shallow binding pocket at the catalytic site, making development of inhibitors difficult. We have designed, preorganized, and depeptidized macrocyclic inhibitors from P(4) to P(2)' and optimized binding to 0.1 microM. The structure of an inhibitor bound to the enzyme was also solved.

Exploring the P2 and P3 ligand binding features for Hepatitis C virus NS3 protease using some 3D QSAR techniques

“…Other conserved features are a negatively charged residue in the P6 position, an alanine or a serine in P1' and a hydrophobic residue in P4' position [19]. The corresponding binding subsites on the enzyme surface are denoted as S6 through S4' [20]. Many of the NS3 inhibitors designed are decapeptide or hexapeptide substrate analogues of the N-terminal cleavage (P6-P1) product [21].…”

The Synthesis of Macrocycles for Drug Discovery

“…236 Similarly, key biphenyl intermediates 132 and 133 ( Figure 11.14, site of ring closure and ruthenium species indicated) for the preparation of HCV NS3/4A protease inhibitors were accessed utilizing this particular cyclization methodology. [237][238][239] For these S N Ar reactions, the organometallic complex, typically prepared from CpRu(CH 3 CN) 3 + PF 6 À , must be used in stoichiometric quantities in order to activate the ring to nucleophilic attack. In addition, the transformation needs to be conducted under high dilution conditions, while the Ru is subsequently removed by photolysis.…”

Macrocyclic inhibitors of HCV NS3 protease

“…The first-generation P 2 -P 4 analogues were synthesized using aliphatic P 2 moieties or a meta-tyrosine derived P 2 with either an aliphatic P 4 linker or a phenylalanine P 4 linker (Figure 3) [33][34]. These compounds spanned from P 3 -P 2 ′ and showed excellent enzyme binding with modest cellular activities (EC 90 = 2 -10 μM).…”