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Protein splicing
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== Applications in Antimicrobial Development == Over the last twenty years, there has been increasing interest in leveraging inteins for [[antimicrobial]] applications.<ref name=":0">{{Cite journal |last1=Tharappel |first1=Anil Mathew |last2=Li |first2=Zhong |last3=Li |first3=Hongmin |date=2022 |title=Inteins as Drug Targets and Therapeutic Tools |journal=Frontiers in Molecular Biosciences |volume=9 |page=821146 |doi=10.3389/fmolb.2022.821146 |issn=2296-889X |pmc=8861304 |pmid=35211511 |doi-access=free }}</ref> Intein splicing is found exclusively in unicellular organisms, with a particularly high abundance in pathogenic microorganisms.<ref>{{Cite journal |last1=Shah |first1=Neel H. |last2=Muir |first2=Tom W. |date=2013-12-24 |title=Inteins: nature's gift to protein chemists |journal=Chemical Science |language=en |volume=5 |issue=2 |pages=446–461 |doi=10.1039/C3SC52951G |issn=2041-6539 |pmc=3949740 |pmid=24634716}}</ref> Furthermore, inteins are commonly found within housekeeping proteins and/or proteins involved in the survival of the organism within a human host. Post-translational intein removal is necessary for the protein to properly fold and function. For example, Gaëlle Huet ''et al.'' demonstrated that in ''[[Mycobacterium tuberculosis]]'', unspliced SufB prevents the formation of the SufBCD complex, a component of the SUF machinery.<ref>{{Cite journal |last1=Huet |first1=Gaëlle |last2=Castaing |first2=Jean-Philippe |last3=Fournier |first3=Didier |last4=Daffé |first4=Mamadou |last5=Saves |first5=Isabelle |date=May 2006 |title=Protein Splicing of SufB Is Crucial for the Functionality of the Mycobacterium tuberculosis SUF Machinery |journal=Journal of Bacteriology |language=en |volume=188 |issue=9 |pages=3412–3414 |doi=10.1128/JB.188.9.3412-3414.2006 |issn=0021-9193 |pmc=1447444 |pmid=16621837}}</ref> As such, the inhibition of intein splicing may serve as a powerful platform for the development of antimicrobials. Current research on intein splicing inhibitors has focused on developing [[antimycobacterial]]s (''M. tb.'' has three intein-containing proteins), as well as agents active against pathogenic fungi ''[[Cryptococcus]]'' and ''Aspergillus.''<ref name="Wall 2021"/> Cisplatin and similar platinum-containing compounds inhibit splicing of the ''M. tb.'' RecA intein through coordinating to catalytic residues.<ref>{{Cite journal |last1=Chan |first1=Hon |last2=Pearson |first2=C. Seth |last3=Green |first3=Cathleen M. |last4=Li |first4=Zhong |last5=Zhang |first5=Jing |last6=Belfort |first6=Georges |last7=Shekhtman |first7=Alex |last8=Li |first8=Hongmin |last9=Belfort |first9=Marlene |date=October 2016 |title=Exploring Intein Inhibition by Platinum Compounds as an Antimicrobial Strategy |journal=Journal of Biological Chemistry |volume=291 |issue=43 |pages=22661–22670 |doi=10.1074/jbc.m116.747824 |issn=0021-9258 |pmc=5077202 |pmid=27609519 |doi-access=free }}</ref> Divalent cations, such as copper (II) and zinc (II) ions, function similarly to reversibly inhibit splicing.<ref name=":0" /> However, neither of these methods are currently suitable for an effective and safe antibiotic. The fungal Prp8 intein is also inhibited by divalent cations and cisplatin through interfering with the catalytic Cys1 residue.<ref name=":0"/> In 2021, Li ''et al.'' showed that small molecule inhibitors of Prp8 intein splicing were selective and effective at slowing the growth of [[Cryptococcus neoformans|''C. neoformans'']] and [[Cryptococcus gattii|''C. gattii'']], providing exciting evidence for the antimicrobial potential of intein splicing inhibitors.<ref>{{Cite journal |last1=Li |first1=Zhong |last2=Tharappel |first2=Anil Mathew |last3=Xu |first3=Jimin |last4=Lang |first4=Yuekun |last5=Green |first5=Cathleen M. |last6=Zhang |first6=Jing |last7=Lin |first7=Qishan |last8=Chaturvedi |first8=Sudha |last9=Zhou |first9=Jia |last10=Belfort |first10=Marlene |last11=Li |first11=Hongmin |date=2021-01-12 |title=Small-molecule inhibitors for the Prp8 intein as antifungal agents |journal=Proceedings of the National Academy of Sciences |language=en |volume=118 |issue=2 |pages=e2008815118 |doi=10.1073/pnas.2008815118 |issn=0027-8424 |pmc=7812778 |pmid=33397721 |bibcode=2021PNAS..11808815L |doi-access=free }}</ref>
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