Delving into the Latest Updates on BILD-733 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target-

Mechanism-

Therapeutic Areas

Infectious DiseasesSkin and Musculoskeletal Diseases

Active Indication-

Inactive Indication

Herpes Simplex

Originator Organization

Boehringer Ingelheim International GmbH

Active Organization-

Inactive Organization

Boehringer Ingelheim International GmbH

Drug Highest PhaseDiscontinuedDiscovery

First Approval Date-

Regulation-

Herpes simplex virus (HSV) encodes a ribonucleotide reductase which provides high levels of deoxynucleotides necessary for replication of viral DNA in infected cells. The enzyme is composed of two distinct subunits, R1 and R2, whose association is required for enzymatic activity. Compounds that mimic the C-terminal amino acids of the HSV ribnucleotide reductase R2 subunit inhibit the enzyme by preventing the association of R1 and R2. Moderate resistance to one of these inhibitors, BILD 733, has been generated in cell culture. This resistance is the result of two point mutations in R1, P1090L and A1091S. Here we report on the binding of additional peptidomimetic inhibitors with altered functional groups to these mutants. This study has made it possible, in the absence of a crystal structure for this enzyme, to define the molecular mechanism by which these two mutations cause the observed resistance. Mutation of proline 1090 to leucine causes a conformational shift in the R1 inhibitor binding site. Mutation of alanine 1091 to serine weakens a specific binding interaction with the hydrophobic carboxy terminus of both R2 and inhibitors. Potential limitations on the degree of viral resistance possible by each resistance mechanism are discussed.

100 Deals associated with BILD-733

Login to view more data