Development of a New Class of Inhibitors for the Malarial Aspartic Protease Plasmepsin II Based on a Central 7‐Azabicyclo[2.2.1]heptane Scaffold

Abstract

Dedicated to Professor Andrea Vasella on the occasion of his 60th birthdayPlasmepsin II (PMII), a malarial aspartic protease involved in the catabolism of hemoglobin in parasites of the genus Plasmodium, and renin, a human aspartic protease, share 35% sequence identity in their mature chains. Structures of 4-arylpiperidine inhibitors complexed to human renin were reported by Roche recently. The major conformational changes, compared to a structure of renin, with a peptidomimetic inhibitor were identified and subsequently modeled in a structure of PMII (Fig. 1). This distorted structure of PMII served as active-site model for a novel class of PMII inhibitors, according to a structure-based de novo design approach (Fig. 2). These newly designed inhibitors feature a rigid 7-azabicyclo[2.2.1]heptane scaffold, which, in its protonated form, is assumed to undergo ionic H-bonding with the two catalytic Asp residues at the active site of PMII. Two substituents depart from the scaffold for occupancy of either the S1/S3 or S2'-pocket and the hydrophobic flap pocket, newly created by the conformational changes in PMII. The inhibitors synthesized starting from N-Boc-protected 7-azabicyclo[2.2.1]hept-2-ene (6; Schemes 1 ± 5) displayed up to single-digit micromolar activity (IC 50 values) toward PMII and good selectivity towards renin. The clear structureÀactivity relationship (SAR; Table) provides strong validation of the proposed conformational changes in PMII and the occupancy of the resulting hydrophobic flap pocket by our new inhibitors.

Plasmepsins as potential targets for new antimalarial therapy

“…97 Encouraged by the high-sequence homology between renin and Plm II, as well as the substantial interdomain flexibility of Plm II 81 and the conformational flexibility indicated by the proPlm II crystal structure (1PFZ), 148 researchers from ETH Zürich modeled the conformational changes observed in renin onto the X-ray structure of Plm II (1SME). 149 This modified Plm II structure was subsequently used for rational design of nonpeptide inhibitors. [149][150][151] Three major binding pockets were recognized: a large hydrophobic S1-S3 pocket (Phe120, Phe111, Met15), a more hydrophilic S2 0 pocket (Leu131, Tyr192), and a new large lipophilic flap pocket.…”

“…149 This modified Plm II structure was subsequently used for rational design of nonpeptide inhibitors. [149][150][151] Three major binding pockets were recognized: a large hydrophobic S1-S3 pocket (Phe120, Phe111, Met15), a more hydrophilic S2 0 pocket (Leu131, Tyr192), and a new large lipophilic flap pocket. Using the molecular-modeling program MOLOC, 7-azabicyclo[2.2.1]heptane was identified as a suitable central scaffold (e.g., inhibitor (þ)-48, Table I).…”

“…By analogy with the renin 4-arylpiperidine inhibitors from Roche 147 the protonated N-atom of the bicyclic structure was predicted to form ionic H-bonds to the catalytic aspartic acids. 149 In order to keep the molecular weight low only substituents in the C(2) and C(3) positions were investigated. Depending on the enantiomer, one of the C(2) and C(3) substituents was predicted to occupy the S1-S3 pocket or the S2 0 pocket, and the other was expected to bind to the newly created flap pocket.…”

Aushungern des Malaria‐Erregers: Hemmer der Aspartylproteasen Plasmepsin I, II und IV

“…[11][12][13] Wir berichten hier über Aufbau und Funktionalisierung eines neuen bicyclischen Diamingerüsts, das wie eine Klammer Wasserstoffbrücken zu den beiden katalytischen Aspartatresten bildet (Abbildung 1 c). Dabei bietet die exo-Aminogruppe zusätzlich einen Abbildung 1.…”

Computer‐Aided Design and Synthesis of Nonpeptidic Plasmepsin II and IV Inhibitors

“…Moreover, there are some reported cases in which docking failed to predict reasonable binding modes based on previously determined crystal structures. [35,36,38] The situation appears even worse for P. falciparum Plm IV, as for this enzyme only a single co-crystal structure in complex with pepstatin A is available (PDB code: 1LS5). For Plm I, only one homology model has been described so far.…”