No abstract

The ability of RNA to catalyze RNA ligation is critical to its central role in many prebiotic model scenarios, in particular the copying of information during self‐replication. Prebiotically plausible ribozymes formed from short oligonucleotides can catalyze reversible RNA cleavage and ligation reactions, but harsh conditions or unusual scenarios are often required to promote folding and drive the reaction equilibrium towards ligation. Here, we demonstrate that ribozyme activity is greatly enhanced by charge‐mediated phase separation with poly‐L‐lysine, which shifts the reaction equilibrium from cleavage in solution to ligation in peptide‐RNA coaggregates and coacervates. This compartmentalization enables robust isothermal RNA assembly over a broad range of conditions, which can be leveraged to assemble long and complex RNAs from short fragments under mild conditions in the absence of exogenous activation chemistry, bridging the gap between pools of short oligomers and functional RNAs.

Intracellular regulatory pathways are replete with protein-protein and protein-DNA interactions, offering attractive targets for therapeutic interventions. So far, most drugs are targeted toward enzymes and extracellular receptors. Protein-protein and protein-DNA interactions have long been considered as “undruggable”. Protein-DNA interactions, in particular, present a difficult challenge due to the repetitive nature of the B-DNA. Recent studies have provided several breakthroughs; however, a design methodology for these classes of inhibitors is still at its infancy. A dominant motif of these macromolecular interactions is an α-helix, raising possibilities that an appropriate conformationally-constrained α-helical peptide may specifically disrupt these interactions. Several methods for conformationally constraining peptides to the α-helical conformation have been developed, including stapling, covalent surrogates of hydrogen bonds and incorporation of unnatural amino acids that restrict the conformational space of the peptide. We will discuss these methods and several case studies where constrained α-helices have been used as building blocks for appropriate molecules. Unlike small molecules, the delivery of these short peptides to their targets is not straightforward as they may possess unfavorable cell penetration and ADME properties. Several methods have been developed in recent times to overcome some of these problems. We will discuss these issues and the prospects of this class of molecules as drugs.

A peptide-based cell permeable synthetic transcription factor is reported, which binds to its target site with high affinity and specificity. When linked to a HAT-binding peptide, it causes significant upregulation of gene expression in a mammalian cell. Such molecules may be developed for selectively activating repressed genes in mammalian cells.

Artificial cells are developed to redesign novel biological functions in a programmable and tunable manner. Although it aims to reconstitute living cell features and address ‘origin of life' related questions, rapid development over the years has transformed artificial cells into an engineering tool with huge potential in applied biotechnology. Although the application of artificial cells was introduced decades ago as drug carriers, applications in other sectors are relatively new and could become possible with the technological advancement that can modulate its designing principles. Artificial cells are non-living system that includes no prerequisite designing modules for their formation and therefore allow freedom of assembling desired biological machinery within a physical boundary devoid of complex contemporary living-cell counterparts. As stimuli-responsive biomimetic tools, artificial cells are programmed to sense the surrounding, recognise their target, activate its function and perform the defined task. With the advantage of their customised design, artificial cells are being studied in biosensing, drug delivery, anti-cancer therapeutics or artificial photosynthesis type fields. This mini-review highlights those advanced fields where artificial cells with a minimalistic setup are developed as user-defined custom-made microreactors, targeting to reshape our future ‘life'.