Structure-Guided Design of C₂-Symmetric HIV-1 Protease Inhibitors Based on a Pyrrolidine Scaffold

Abstract

Infections with the human immunodeficiency virus, which inevitably lead to the development of AIDS, are still among the most serious global health problems causing more than 2.5 million deaths per year. In the pathophysiological processes of this pandemic, HIV protease has proven to be an invaluable drug target because of its essential role in the virus' replication process. By use of pyrrolidine as core structure, symmetric 3,4-bis-N-alkylsulfonamides were designed and synthesized enantioselectively from D-(-)-tartaric acid as a new class of HIV protease inhibitors. Structure-guided design using the cocrystal structure of an initial lead as starting point resulted in a second series of inhibitors with improved affinity. The binding modes of four representatives were determined by X-ray crystallography to elucidate the underlying factors accounting for the SAR. With this information for further rational design, the combination of suitable side chains resulted in a final inhibitor showing a significantly improved affinity of K(i) = 74 nM.

Structural and Kinetic Analysis of Pyrrolidine-Based Inhibitors of the Drug-Resistant Ile84Val Mutant of HIV-1 Protease

“…The co-crystal structures of six derivatives were determined in complex with wild-type HIV-1 protease {compound [Protein Data Bank (PDB) ID]: 1 (2PQZ), 3 (2QNP), 6 (2QNQ), 8 (2PWC), 9 (2PWR), 10 (2QNN); Table 2} and further utilized within a structure-guided optimization process. 12 These crystal structures revealed a conserved binding mode for all investigated derivatives, schematically represented in Fig. 1: The endocyclic amino function addresses the catalytic dyad and a unique flap interaction pattern is observed.…”

Two Solutions for the Same Problem: Multiple Binding Modes of Pyrrolidine-Based HIV-1 Protease Inhibitors

“…9 Recently, we reported our design and synthesis of C 2 -symmetric 3,4-disubstituted pyrrolidines as a new class of human immunodeficiency virus type 1 (HIV-1) protease inhibitors. 10 Our structureguided optimization was based on the initially observed cocrystal structure of the N-benzylsubstituted inhibitor (3S,4S)-3,4-bis[benzenesulfonylbenzylamino]pyrrolidine (1) (PDB ID: 2PQZ; Fig. 1 and Table 1).…”

Pyrrolidine Derivatives as Plasmepsin Inhibitors: Binding Mode Analysis Assisted by Molecular Dynamics Simulations of a Highly Flexible Protein

“…Bis-benzylated pyrrolidine 5: Powdered molecular sieves (4 , 0.65 g) and benzaldehyde (0.79 mL, 7.8 mmol) were added to a solution of tert-butyl-(3S,4S)-3,4-diaminopyrrolidine-1-carboxylate [49] (0.52 g, 2.6 mmol) in dry MeOH at room temperature. The suspension was stirred for 1 h under Ar.…”