Abstract
Multidrug-resistant pathogens are of significant concern in recent years. Hence new antifungal and anti-bacterial drug targets are urgently needed before the situation goes beyond control. Inteins are polypeptides that self-splice from exteins without the need for cofactors or external energy, resulting in joining of extein fragments. Inteins are present in many organisms, including human pathogens such as Mycobacterium tuberculosis, Cryptococcus neoformans, C. gattii, and Aspergillus fumigatus. Because intein elements are not present in human genes, they are attractive drug targets to develop antifungals and antibiotics. Thus far, a few inhibitors of intein splicing have been reported. Metal-ions such as Zn2+ and Cu2+, and platinum-containing compound cisplatin inhibit intein splicing in M. tuberculosis and C. neoformans by binding to the active site cysteines. A small-molecule inhibitor 6G-318S and its derivative 6G-319S are found to inhibit intein splicing in C. neoformans and C. gattii with a MIC in nanomolar concentrations. Inteins have also been used in many other applications. Intein can be used in activating a protein inside a cell using small molecules. Moreover, split intein can be used to deliver large genes in experimental gene therapy and to kill selected species in a mixed population of microbes by taking advantage of the toxin-antitoxin system. Furthermore, split inteins are used in synthesizing cyclic peptides and in developing cell culture model to study infectious viruses including SARS-CoV-2 in the biosafety level (BSL) 2 facility. This mini-review discusses the recent research developments of inteins in drug discovery and therapeutic research.
Highlights
Prolonged use of drugs can lead to drug-resistant strains of pathogens and is a major challenge in treating the diseases
The exact functions of inteins remain elusive, splicing of intein from exteins is essential for activity of the intein-harboring protein
Many bacterial and fungal pathogens harbor inteins in their essential proteins
Summary
Prolonged use of drugs can lead to drug-resistant strains of pathogens and is a major challenge in treating the diseases. The active site is formed by folding of intein within the precursor, resulting in splice junctions (Tori et al, 2010). Based on the splicing mechanisms, there are three classes of inteins (Tori et al, 2010; Nanda et al, 2020). The class I intein splicing consists of four coordinated nucleophilic displacement reactions. The class III inteins form a specific Block F branched intermediate with Cys at block F as the branch point before arrive at the Block G branched intermediate (Tori and Perler, 2011a). The active site residues and positions within the intein vary in each classes (Tori and Perler, 2011b). The causative agent M. tuberculosis has one intein in each of the three M. tuberculosis proteins: replicative helicase (DnaB), recombinase (RecA), and an iron-sulfur cluster assembly (SufB) (Topilina et al, 2015).
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
