Strecker-type reactions and MSAS as tools for protease inhibitor discovery

In this work, two aspects of fragment-based lead discovery were explored: (1) a screening method to find a bioisosteric replacement for the carboxylate of a caspase-1 inhibitor; and (2) a protocol for a one pot reaction for combining fragment-like molecules into small inhibitor-like molecules. MSAS was developed in our group by colleagues as an improvement to SAS. MSAS advantage is to identify false negatives that are missed during the substrate screening. This was fundamental to identify isosteres since the library used did not contain any caspase substrates. The new analogues had higher IC50 values for caspase-1 than VRT-043198. One analogue had an IC50 in the nanomolar range, which would be worth to study further to determine if the bioisostere confers the molecule other advantages. The one pot protocol for a Strecker-like reaction to produce N-acylated α-amino nitriles was based on reports from the literature where similar reactions are achieved in two-step manner. We developed and optimized to a certain extent one reaction, and then explored the possibility of producing a diverse library of peptide-like compounds. These compounds are potential mechanism-based inhibitors of proteases. Other similar reactions were explored in a more superficial way; however, it might be worth further research. In conclusion, we were able to demonstrate the versatility of the MSAS and develop a flexible one pot reaction to synthesize N-acylated α-amino nitriles.

Publication year:2021

Keywords:Doctoral thesis

Accessibility:Open