Synthetic polymers self-assembling into catalytic structures

Modern organic chemists have access to a huge range of different chemical reactions and, these days, even the most complicated natural product could probably be synthesised if somebody wanted to. However, nature still does chemistry a hell of a lot better than even the best organic chemist; enzymes allow even the simplest organism to catalytically (and often asymmetrically) carry out organic reactions at room temperature in an aqueous environment. Being able an enzyme’s characteristics artificially would be, obviously, hugely advantageous. And there are a number of project on-going particularly using supramolecular chemistry, dendrimers or polymers. Another method, one of the first in a completely aqueous environment, has been described in a short communication in Angerwandte by the Palmans group. It utilises a simple polymer functionalised with L-proline allowing it to diastereoselectively catalyse an aldol reaction with cyclohexanone and p-nitrobenzaldehyde.

Reversible covalent inhibitors: the best of both worlds?

What’s not to love about covalent inhibitors? Well, unfortunately, quite a bit when you start thinking about it. Reversible inhibitors offer an extra layer of subtlety, they are tuneable, time-dependent and can modulate individual functions of proteins or biological systems by using several inhibitors in combination. That is as long as you can make them potent and selective enough; covalent inhibitors tend to solve the first problem in spades, once you make your covalent bond it’s staying there usually knocking out the enzyme target. Yet the greatest strength is the greatest weakness, unfortunately by improving the potency of your compounds the problems with selectivity are multiplied. If your covalent inhibitor goes to the wrong protein first well tough; this great if you’re a beta-lactam antibiotic trying to kill a bacterium, but killing things isn't what tool compounds are for. 

But what if you could make a reversible covalent inhibitor? Potentially you could gain the potency and, if well designed, the selectivity as well. Maybe this would still be difficult to incorporate into a drug, but as a basis for a sophisticated tool compound it could be extremely useful. Taunten et.al. have developed such a system that targets the amino acid cysteine. 

A non-functioning tool? - when’s the next paper?

This paper from Feringa’s Lab caught our eye.  The paper demonstrates the ability to incorporate azobenzene photoswitches onto sites of interest through a bio-orthogonal reaction.  The group synthesised two azobenzenes (Figure 1), one with a short PEG motif and one without, evaluated their physical properties when ligated to various targets.

Shaking Up Small Molecule Binding

I’ll be honest I thought I knew a fair bit about small molecules binding to proteins. If someone asked me what a phenyl ring in a molecule was doing I could talk earnestly about the entropic effect of displacing those water molecules, stacking interactions, Van der Waals forces, maybe even pi-charge interactions. I could have also talked about hydrogen-bonding and I would have certainly mentioned the hydrophobic effect (mind you that is more complicated than it looks sometimes) and how a molecule rotates (i.e. the less carbon chains and more rings the better).

One thing I certainly would not have mentioned was how individual bonds vibrate, but what do I know? 2 recent papers talking about deuterium effecting how compounds smell  and another using the IR spectra of nitrile groups to explain the observed binding affinity of a family of HIV drugs demonstrate how what I think I know and what I actually know are sometimes a disappointing distance apart.

Bio-orthogonal profiling of protein methylation

Protein methylation is an important biological process e.g. histone lysine methylation is involved in both gene activation (on histone 3 and Lys 4, 36 and 79) and silencing (H3 Lys 9 or 27 and H4 Lys 20). But how can other protein methyltransferases (PMTs) be investigated? Genetic approaches are always useful, but can have limitations particularly if your protein isn’t very common, forms complexes with other proteins (which would be disrupted by its absence and cause phenotypic changes beyond protein methylation) or if your process results in a non-viable cell. Chemical approaches would be extremely useful and complimentary, but as always problems with selectivity have to be overcome; a particular problem with PMTs as SAM (S-Adenosyl methionine) is a particularly prolific enzyme co-factor.

What to do then? Islam et. al. have developed a rather elegant solution that could allow general examination of a variety of PMTs, by creating mutants of proteins that can accept a synthetic azido-SAM donor. The enzyme then tags its target as before but instead of a methyl an azide containing group is left behind, this can subsequently be reacted with tags (like biotin) which contain strained alkynes in a bio-orthogonal manner.