Friday, 21 October 11:00am – 12:00pm

This seminar will be delivered in Chemistry Lecture Theatre 4 and Online Zoom. Please email chemistry.researchsupport@sydney.edu.au for zoom link and password.

Speaker: Dr Christoph Nitsche; Australian National University (ANU)

Host: Prof. Liz New

Title: Targeting viral proteases with modified peptides

Abstract: Many RNA viruses use the host-cell ribosomal machinery to translate their genome but employ viral proteases to cleave the polyproteins into its active constituents. Therefore, viral proteases are essential for viral replication and thus excellent drug targets. Many viral protease inhibitors in clinical use are modified peptide substrate analogues. Examples are approved drugs against HIV, hepatitis C virus (HCV), and the recently approved SARS-CoV-2 main protease inhibitor nirmatrelvir.

Our research targets proteases from pathogenic flavi-, alpha- and coronaviruses and aims to develop broad-spectrum peptide-based inhibitors. Peptides may be derived from the substrate recognition sequence or identified de novo. We have a particular interest in peptide modifications that can (i) enhance metabolic stability by greater resistance towards proteolysis, (ii) promote biological uptake across cell membranes, (iii) allow for covalent interaction, and (iv) decrease the entropic penalty of binding by locking the peptide in the active conformation.

After initial studies with covalently binding peptides of limited stability and selectivity, we explored constrained peptides as promising alternatives. We developed different peptide cyclisation and stapling strategies using a biocompatible nitrile-aminothiol click reaction and bismuth-cysteine interaction. Using these approaches in small screening campaigns, we were able to identify various active cyclic and bicyclic peptides with improved proteolytic and plasma stability. Combination with cell-penetrating peptide sequences allowed for further advancement. In addition, we discovered macrocyclic peptides with novel binding modes using mRNA display screenings.

Biography: Christoph Nitsche completed his PhD at Heidelberg University in 2014 supported by the German Academic Scholarship Foundation. He was awarded a Feodor Lynen Fellowship (Alexander von Humboldt Foundation) to work at the Australian National University from 2015 to 2018, followed by a period as Rising Star Fellow at the Free University of Berlin. In 2019, he returned to the ANU as an ARC DECRA Fellow and was appointed Senior Lecturer in 2020. He received an ARC Future Fellowship in 2022. His research program focuses on drug discovery against infectious diseases, biocompatible chemistry, and peptide and protein modification.