Prebiotic chemistry: a review of nucleoside phosphorylation and polymerization

The phosphorylation of nucleosides and their polymerization are crucial issues concerning the origin of life. The question of how these plausible chemical processes took place in the prebiotic Earth is still perplexing, despite several studies that have attempted to explain these prebiotic processes. The purpose of this article is to review these chemical reactions with respect to chemical evolution in the primeval Earth. Meanwhile, from our perspective, the chiral properties and selection of biomolecules should be considered in the prebiotic chemical origin of life, which may contribute to further research in this field to some extent

A Practical Method for Amino Acid Analysis by LC-MS Using Precolumn Derivatization with Urea

Amino acid (AA) analysis is important in biochemistry, food science, and clinical medicine. However, due to intrinsic limitations, AAs usually require derivatization to improve their separation and determination. Here, we present a liquid chromatography-mass spectrometry (LC-MS) method for the derivatization of AAs using the simple agent urea. The reactions proceed quantitatively under a wide range of conditions without any pretreatment steps. Urea-derivatized products (carbamoyl amino acids) of 20 AAs exhibit better separation on reversed-phase columns and increased response in a UV detector compared to underivatized ones. We applied this approach to AA analysis in complex samples using a cell culture media as a model, and it showed potential for the determination of oligopeptides. This fast, simple, and inexpensive method should be useful for AA analysis in complex samples

Cu(II)-Assisted Novel Covalent Warheads for Proteome-wide Cysteine Profiling

In the realm of residue-specific labeling of amino acids within the proteome, cysteine (-SH) emerges as a particularly nucleophilic residue and plays a pivotal role in covalent drug discovery. Despite significant strides in targeting cysteine sites, there remains a substantial expanse of unexplored site space. We discovered that a nucleophilic phenol (DBA)/Cu2+ ‘complex’ serves as a potent warhead for traditionally "inert" cysteines. In the context of a general chemoproteomics profiling, the DBA-1 probe exhibits higher reactivity than IAA toward approximately 45% of quantifiable Cys sites. Dose-dependent profiling experiments suggest that Cu2+ may function not only as an oxidizing agent of phenol but also as a chelating agent of polar residues in proteins. Given its reliance on structural characteristics of proteins for site targeting, this novel (DBA)/Cu2+ ‘complex’ fits the scope of ‘structure-based protein profiling’ (SBPP), highlighting the role of metal ion in the design of effective warheads and the virtue of new proteomic microenvironmental chemistry ‘hunting’

Evaluation of Site-Diversified, Fully Functionalized Diazirine Probes for Chemical Proteomic Applications

Photoaffinity probes combined with the chemical proteomic platform have emerged as versatile tools for ligand and target discovery. However, photoaffinity probes with retained activity cannot always label the known target, indicating that it is challenging to profile a ligand’s targets based on its photoaffinity probe modified at a single site. Herein, we construct a series of site-diversified probes (P1-P6) of 4-anilinoquinazoline, a scaffold shared by several marketed EGFR-targeted drugs, via attaching a “fully functionalized” diazirine tag to six different sites, respectively. Chemical proteomic analysis revealed that these probes show different proteome-wide profiles and distinct competition patterns by erlotinib. Remarkably, low activity P4 towards EGFR inhibition has better EGFR labelling efficiency than the higher one, P5, which highlights the dominance of labelling accessibility of diazirine over probe affinity. In addition, the integrated analysis of protein targets of site-diversified probes can also help distinguish false positive targets. We anticipate that site-diversification of the probes of a given scaffold is an indispensable strategy to truly harness the power of photoaffinity-based chemoproteomics in drug discovery