One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Chan, Wai Ting; Balsa, Dolors; Espinosa, Manuel

Another line of work made use of a typifying characteristic of viral proteases, which have very specific cleavage site, to target explicitly the infected cells instead of the innocent ones (Park, Yamaguchi and Inouye 2012) . Non-structural serine protease, NS3-4A, is an HCV protein that is essential for the HCV replication. An NS3-activated MazF system was constructed in which the NS3 protease cleavage site linker was fused in between MazF and truncated C-terminal of MazE (as we interpret in Fig. 2b ). These fusion proteins are inert, and when incubated with NS3 protease the MazF toxin could be activated via cleavage at the linker in between MazE and MazF complex (Park, Yamaguchi and Inouye 2012) . Other viral protease cleavage sites worked the same with their corresponding proteases (e.g. HIV-1 protease and factor Xa) (Park, Yamaguchi and Inouye 2012) . A similar construct was done by another group which they termed it as 'zymoxin' (Shapira et al., 2012) . While this construct was activated by NS3 protease (in HEK293 T-REx cells that harbour tetracycline-inducible NS3-4A constructs), NS3-mediated activation of MazF that inhibited cellular protein synthesis was observed; however, cytotoxic effect was also evident even when NS3 was mildly induced (Shapira et al., 2012) . The possible undesirable effects of MazF cleaving the eukaryotic mRNAs could be avoided by careful control of the dosage of the toxin, so that MazF was able to cleave the viral, but not damaging the cells (Chono et al., 2011a,b) .