Antiviral and Antivirulence Drugs
Work in the Empting lab focuses on tackling innovative and difficult-to-address anti-infective targets such as bacterial virulence regulatory systems as well as un(der)explored anti-herpesviral persitance mediators. By this, we aspire to circumvent common resistance mechanisms and to refill the dried out development pipeline. This group is located at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)
We progress our antiinfective projects through all the stages of drug discovery. Our hit-finding strategies are selected individually for the target molecule at hand. In the case of receptors and enzymes with pockets druggable with small molecules (e.g. PqsR, PqsE), we employ fragment-based methodologies and transform identified starting points (hits) into drug-like molecules (leads) by medicinal chemistry optimization. In this regard, we follow a multi-parameter optimization considering not only potency but also pharmacokinetic and safety pharmacology endpoints. Ideally, leads are optimized towards preclinical profiling candidate status in order to facilitate preclinical development.
Difficult-to-drug macromolecule-macromolecule interactions provide challenging, yet, promising and notoriously underexploited points of disease intervention. We have been successful in applying above-mentioned fragment-based hit identification to a protein-DNA interaction essential for the lifecycle of human herpesvirus 8 (Kaposi´s sarcoma herpesvirus, KSHV) mediated by the latency-associated nuclear antigen (LANA). In order to supplement and complement these small molecule-directed approaches, we also apply the phage display technology for the screening of very short macrocyclic (constrained) peptide sequences. The resulting hits are readily synthetically accessible starting points amenable to medicinal chemistry optimization towards novel drug molecules at the boarders of Lipinski´s rule of five (or just slightly beyond). In the future, we aim to combine fragment- and phage-display-based approaches to generate peptide-small molecules hybrids with the aim to explore currently untapped chemical space.