Hi Pete
I agree that it is usually easier to optimise reversible inhibitors, which should be the first priority. However, success is not guaranteed. Covalent inhibitors could offer a useful alternative and I feel also should be pursued. As well as higher degrees of target engagement, they could give longer residence time with PD possibly extending beyond PK if clearance is rapid. If so, this may give reduced off-target toxicity.
All the best
Wal
Thanks for the reference Pete, one to add to my PPB collection, we have a cysteine protease panel lined up with Nanosyn.
Hi Wal,
Just as a point of clarification, I was not arguing against covalent inhibitors. Compounds such as odanacatib, balicatib and petesicatib delivered by industrial cathepsin inhibitor projects can be described as peptidomimetic and targeting catalytic cysteine covalently with a ‘reversible’ warhead (typically nitrile). This is the direction in which I’d be looking if I was setting up a project against a cysteine protease project. My view is that it will not be possible to (rapidly) discover a compound that combines high affinity with good physicochemical/pharmacokinetic characteristics unless the cysteine is targeted (I would be very happy to be proven wrong on this point). The two designs that I’ve submitted to the Moonshot project both seek to link a fragment-derived inhibitor to a ‘reversible’ warhead.
Arguments presented in support of irreversible inhibitors tend to parallel those presented in support of slow off-rates and this article by our former colleague Rutger may be of interest (apologies if I’ve flagged it up already):
http://dx.doi.org/10.1016/j.drudis.2017.07.016
While engagement of target by an inhibitor that is irreversible (or has slow binding kinetics) will persist during the elimination phase, the peak target engagement level will typically be lower than for an inhibitor with fast binding kinetics. I am not especially familiar with immunology although it is my understanding that there would be safety concerns about drugs binding irreversibly to extracellular proteins or remaining bound to peptide fragments after intracellular protein has been degraded.
Given the greater degree of complexity associated with design and evaluation of irreversible inhibitors, I think that it’d be a good idea to see if the GSH stability assay can be used to assess clearance.
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Hi Ed, I’d be interested in the composition of the cysteine protease panel. Something that may be of interest is that the peptidomimetic inhibitors tend to bind to SARS-CoV-2 with a binding mode that differs from the ‘cathepsin binding mode’.