Rudy Edmond Willebrords

Diarylquinolines Are Bactericidal for Dormant Mycobacteria as a Result of Disturbed ATP Homeostasis

An estimated one-third of the world population is latently infected with Mycobacterium tuberculosis. These nonreplicating, dormant bacilli are tolerant to conventional anti-tuberculosis drugs, such as isoniazid. We recently identified diarylquinoline R207910 (also called TMC207) as an inhibitor of ATP synthase with a remarkable activity against replicating mycobacteria. In the present study, we show that R207910 kills dormant bacilli as effectively as aerobically grown bacilli with the same target specificity. Despite a transcriptional down-regulation of the ATP synthase operon and significantly lower cellular ATP levels, we show that dormant mycobacteria do possess residual ATP synthase enzymatic activity. This activity is blocked by nanomolar concentrations of R207910, thereby further reducing ATP levels and causing a pronounced bactericidal effect. We conclude that this residual ATP synthase activity is indispensable for the survival of dormant mycobacteria, making it a promising drug target to tackle dormant infections. The unique dual bactericidal activity of diarylquinolines on dormant as well as replicating bacterial subpopulations distinguishes them entirely from the current anti-tuberculosis drugs and underlines the potential of R207910 to shorten tuberculosis treatment.

Selection of a Respiratory Syncytial Virus Fusion Inhibitor Clinical Candidate. 2. Discovery of a Morpholinopropylaminobenzimidazole Derivative (TMC353121)

A preceding paper (Bonfanti et al. J. Med Chem. 2007, 50, 4572-4584) reported the optimization of the pharmacokinetic profile of substituted benzimidazoles by reducing their tissue retention. However, the modifications that were necessary to achieve this goal also led to a significant drop in anti-RSV activity. This paper describes a molecular modeling study followed by a lead optimization program that led to the recovery of the initial potent antiviral activity and the selection of TMC353121 as a clinical candidate.

Binding of a potent small-molecule inhibitor of six-helix bundle formation requires interactions with both heptad-repeats of the RSV fusion protein

Six-helix bundle (6HB) formation is an essential step for many viruses that rely on a class I fusion protein to enter a target cell and initiate replication. Because the binding modes of small molecule inhibitors of 6HB formation are largely unknown, precisely how they disrupt 6HB formation remains unclear, and structure-based design of improved inhibitors is thus seriously hampered. Here we present the high resolution crystal structure of TMC353121, a potent inhibitor of respiratory syncytial virus (RSV), bound at a hydrophobic pocket of the 6HB formed by amino acid residues from both HR1 and HR2 heptad-repeats. Binding of TMC353121 stabilizes the interaction of HR1 and HR2 in an alternate conformation of the 6HB, in which direct binding interactions are formed between TMC353121 and both HR1 and HR2. Rather than completely preventing 6HB formation, our data indicate that TMC353121 inhibits fusion by causing a local disturbance of the natural 6HB conformation.