Volume 18 Issue 9, September 2022

Controlling kinase inhibitors’ residence time via reversible covalent binding is of high interest in drug discovery. Tuning reversible covalent binding kinetics using a pan-kinase inhibitor that reacts with the catalytic lysine enabled exquisite temporal selectivity in vitro and in vivo.

A directed evolution approach delivers ribosomes with highly functional tethered subunits. Combining the decoding and peptidyl transferase activities of the ribosome into a single entity sets the scene for more efficient protein engineering technologies.

Transposon-associated transposase B (TnpB) is the putative ancestor of Cas nucleases. A TnpB-based adenine base editor has now been developed that is small enough to be loaded into a single AAV vector without compromising editing activity.

Elucidating the interactions between serum protein-bound nanoparticles and cell-surface receptors typically operates on a per protein–receptor interaction basis. Integration of omic approaches for testing thousands of interactions unbiasedly reveals important interactions that drive cellular uptake of nanoparticles.

Loss of myelin causes neurological symptoms for patients with multiple sclerosis. This Perspective details how phenotypic screening has accelerated discovery efforts toward potential ‘remyelinating therapeutics’.

The linking of salicylaldehydes to a kinase binding scaffold resulted in the development of reversible, lysine-targeted covalent kinase inhibitors with enhanced residence time.

MNK2 was identified as the target of a small molecule named CID661578 that can stimulate pancreatic β-cell generation in zebrafish, pig and human organoids. CID661578 prevents MNK2 from binding to eIF4G in the translation initiation complex.

B-cell activation reprograms the TCA cycle and reduces cellular fumarate levels. Increased fumarate caused by fumarase inhibition or dimethyl-fumarate treatment directly succinates and inhibits LYN, leading to impaired B-cell activation and function.

The first crystal structure of human TMPRSS2, a proteolytic driver of SARS-CoV-2 infection in airways and an antiviral target, reveals structural features of viral spike protein and protease inhibitor binding.

Using combined methods of modern chemical protein synthesis and structural biology, Ai et al. found a crosstalk mechanism of histone modifications, by which H2BK34ub stimulates the activity of the H3K79 methyltransferase Dot1L through inducing nucleosome distortion.

A combined screening and selection approach enables the evolution of the generalist transcription factor RamR into specific and sensitive biosensors for various alkaloids and in turn a streamlined pathway for tetrahydropapaverine biosynthesis.

Evolink, a method developed to co-evolve structurally adjacent but sequence-distant sites in molecular machines, was used in concert with computational modeling to evolve an improved tethered ribosome variant.

The de novo design of a pair of complementary peptides, one basic for cell penetration and target binding and one acidic that can be fused to proteins of interest, provides an approach for delivery into mammalian cells and subcellular targeting.

A hypercompact adenine base editor termed TaRGET-ABE was developed by fusing a catalytically inactive transposon-associated transposase B guided by an engineered RNA to deaminases, which achieves efficient A-to-G conversions via adeno-associated viral delivery in mammalian genomes.

Using single-molecule magnetic tweezers and biochemical methods, Naqvi et al. revealed how CRISPR–Cas12a regulates the DNA cleavage rate through a conserved stacking interaction between the R-loop and the W355 residue and the sequence of the CRISPR RNA 3′ end.

A combination of mass spectrometry, pooled genome screens and STRING analysis identifies key uptake mediating interactions between nanoparticle-adsorbed proteins and cells via the low-density lipoprotein receptor.