Overcoming insecticide resistance through computational inhibitor design

Check out Galen’s latest work on the computational design of reversible covalent picomolar inhibitors of carboxylesterase αE7 – helping to overcome insecticide resistance! The manuscript ‘Overcoming insecticide resistance through computational inhibitor design’ is now available as a preprint on bioRxiv! In this work, done in collaboration with the London lab at the Weizmann Institute of Science, we use covalent computational design to produce nano/pico-molar boronic acid inhibitors of the carboxylesterase αE7 from the agricultural pest Lucilia cuprina, as well as a common Gly137Asp αE7 mutant that confers OP resistance. These inhibitors, with no intrinsic apparent toxicity, act synergistically with the OPs diazinon and malathion to reduce the amount of OP required to kill L. cuprina by up to 16-fold, and abolish resistance. These compounds represent a solution to insecticide resistance. Shoo fly!

New Publication

Nick, Paul and Colin contributed to the recently accepted paper “The Synthesis of Certain Derivatives and Analogues of (–)- and (+)-Galanthamine and an Assessment of their Capacities to Inhibit Acetylcholine Esterase” in The Journal of Organic Chemistry. This work, done in collaboration with the Banwell group at ANU, describes the syntheses of certain di- and mono-oxygenated derivatives and analogues of the alkaloid galanthamine. In contrast to results from docking studies, we show that none of these compounds strongly bind to acetylcholine esterase.

 

New Publication

Congratulations to Paul, Galen and Colin for their work on the paper “Total Syntheses of the Amaryllidaceae Alkaloids Zephycandidine III and Lycosinine A and Their Evaluation as Inhibitors of Acetylcholinesterase”, which was recently accepted to the European Journal of Organic Chemistry. This collaboration with the Banwell Group (ANU) describes the total synthesis of the amaryllidaceae alkaloids Zephycandidine III and Lycosinine A. Contrary to an earlier study, these compounds are shown to be poor inhibitors of acetylcholinesterase. 

Biomolecular Machines Conference

Joe and Matt recently presented their work at the Biomolecular Machines Conference in Banff, Canada. Joe was awarded the prize for the best student talk at the conference. Joe and Matt will be spending the next few weeks working in Nobu Tokuriki’s lab at the University of British Columbia.

New Publication

Colin, Thanavit, Blair and Brendon contributed to the recently published paper entitled “Mycobacterial F420H2-dependent reductases promiscuously reduce diverse compounds through a common mechanism” in Frontiers in Microbiology. This work presents the first broad survey of actinobacterial F420H2-dependent reductases as potential industrial biocatalysts by exploring the extent, as well as mechanistic and structural bases, of their substrate promiscuity. The findings of this work suggest that engineered actinobacterial F420H2-dependent reductases are promising novel biocatalysts for the facile transformation of a wide range of α,β-unsaturated compounds. Top work guys!

New publication

Congratulations to Elena, on the publication of her paper ‘Constrained evolution of a bispecific enzyme: lessons for biocatalyst design’ in Organic and Biomolecular Chemistry. In this work we investigate the impact of intramolecular epistasis on the evolution of atrazine-specific and atrazine/ametryn bispecific triazine hydrolyses (TrzN). Results show that many of the evolutionary trajectories linking the mono-functional and bispecific isoforms are unviable due to inactive intermediates, with the epistatic interactions between mutations being responsible for the bottlenecks in the evolutionary landscape. This work will help guide future work in the design of biocatalysts.

New publications

Congratulations to Ben, Jason, Josh and Will who have recently contributed work to a book entitled ‘Synthetic Protein Switches: Methods and Protocols”. The two chapters describe the protocols that they have developed for creating a range of FRET sensors, including the use of ancestral protein reconstruction, circular permutation and computational modelling. Well done guys!

New Publication

Congratulations to Elena on the publication of her review entitled ‘The evolution of new catalytic mechanisms for xenobiotic hydrolysis in bacterial metalloenzymes’ in Australian Journal of Chemistry. This work was done with collaborators at CSIRO.

In this work, we surveyed the range of xenobiotic-degrading metalloenzymes, and discuss the molecular and catalytic basis for the development of new activities. We also highlight how our increased understanding of the natural evolution of xenobiotic-degrading metalloenzymes can be been applied to laboratory enzyme design.

New Publication

Ben and Colin have recently contributed to a paper entitled ‘Structural reconstruction of protein ancestry’ in PNAS. In this work done with Daniel Christ’s group and other collaborators, laboratory evolution and X-ray crystallography were used to recreate and characterise homodimeric forms of antigen receptors. The findings of this work provide molecular insights and support of long-held theories concerning the evolution of the adaptive immune system. They also provide a blueprint for the experimental reconstruction of ancestral proteins in the large number of cases in which evolution has obscured sequence similarities beyond recognition, and which cannot be analyzed using current sequence-based approaches.

Welcoming Lynn to the Jackson Group

We welcome Lynn Tan to the Jackson Group. Lynn has recently moved up to Canberra from Melbourne, where she was working with Professor Jamie Rossjohn. Her experience in protein expression, purification and biophysical analysis has already been of great benefit to the group. Welcome Lynn!