Protein splicing involves the excision of an intervening polypeptide sequence, the intein, from an inactive precursor protein and the concomitant joining of the flanking sequences, the exteins, by a new peptide bond. Two important proteins of M. tuberculosis, DnaB and RecA, which are essential for DNA replication and DNA repair, respectively, are interrupted by closely related inteins. The excision of these inteins by protein splicing is required for the function of these proteins and the inhibition of protein splicing will therefore be lethal to this parasite. We are developing screening systems for inhibitors of RecA and DnaB intein-mediated protein splicing. Such inhibitors would constitute a new class of anti-mycobacterial drugs which may provide an effective treatment of multi-drug resistant tuberculosis, which is a world-wide health problem.
Paulus, H. (2007) Protein splicing inhibitors as a new class of antimycobacterial agents. Drugs of the Future 32, 973-984. [Download PDF file]
Mills, K.V. and Paulus, H. (2005) Biochemical mechanisms of intein-mediated protein splicing, in “Homing Endonucleases and Inteins” (M. Belfort, V. Derbyshire, B. Stodddard and D. Wood, eds), Springer Verlag, pp. 233-255.
Paulus, H. (2003) Inteins as targets for potential antimycobacterial drugs. Frontiers in Bioscience 8, s1157-1165.
Gangopadhyay, J.P., Jiang, S.-q. and Paulus, H. (2003) In vitro screening system for protein splicing inhibitors based on green fluorescent protein as indicator. Analytical Chem 75, 2456-2462.
Lew BM, Paulus H. (2002) An in vivo screening system against protein splicing useful for the isolation of non-splicing mutants or inhibitors of the RecA intein of Mycobacterium tuberculosis. Gene 282, 169-77.
Paulus, H. (2001) Inteins as enzymes. Bioorg Chem 29, 119-129.
Paulus, H. (2000) Protein splicing and related forms of protein autoprocessing. Annu. Rev. Biochem, 69, 447-96.