XLChen

Nature Materials, Published online: 06 May 2021; doi:10.1038/s41563-021-00993-6

Charged colloidal systems undergo fast crystallization under deep supercooling due to a coupled mechanism involving the discrete advancement of the crystal growth front and defect repair inside the recently formed solid phase.

Conventional thrombolytic drugs for vascular blockage such as tissue plasminogen activator (tPA) are challenged by the low bioavailability, off-target side effects and limited penetration in thrombi, leading to delayed recanalization. We hypothesize that these challenges can be addressed with the targeted and controlled delivery of thrombolytic drugs or precision drug delivery. A porous and magnetic microbubble platform is developed to formulate tPA. This system can maintain the tPA activity during circulation, be magnetically guided to the thrombi, and then remotely activated for drug release. The ultrasound stimulation also improves the drug penetration into thrombi. In a mouse model of venous thrombosis, the residual thrombus decreased by 67.5% when compared to conventional injection of tPA. The penetration of tPA by ultrasound was up to several hundred micrometers in thrombi. This strategy not only improves the therapeutic efficacy but also accelerates the lytic rate, enabling it to be promising in time-critical thrombolytic therapy.

A focused approach: A DNA‐encoded peptoid library was designed by the Ugi multicomponent reaction around indole structures that mimic the side chain of tryptophan. Applying this focused library to the challenging cancer targets MDM2 and hTEAD4 yielded compounds for inhibitor development. Compounds binding to hTEAD4 disrupted the hTEAD4–YAP interaction, and reduced expression of a gene under control of the TEAD–YAP transcription factor complex.

Abstract

DNA‐encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or “hot spot”, regions of protein–protein interactions. A DNA‐encoded combinatorial peptoid library was designed based on the Ugi four‐component reaction by employing tryptophan‐mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide “hexT”, encoded by DNA sequences, and substituted by azide‐alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor‐relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD‐YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors.