One cannot rule them all: Are bacterial toxins-antitoxins druggable?
Bottom Line: The result is a cessation of cell growth or even death.Appropriate fragments could disrupt the T:A interfaces leading to the release of the targeted TA pair.Possible ways of delivery and formulation of Tas are also discussed.
Affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu, 9, 28006-Madrid, Spain.Show MeSH
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Mentions: MazEF is a well-studied TA operon that constitutes an attractive candidate for antivirals. As mentioned above, MazF toxin is an endoribonuclease, which preferentially cleaves single-stranded RNA between A and C residues at the ACA recognition sequence in a manner independent of ribosome and thus inhibiting protein synthesis (Zhang et al., 2003), whereas MazE is its cognate antitoxin which ifies MazF toxicity. There have been, as far as we are aware, a few reports on possible use of MazEF as antivirals (summarized in Fig. 2). The first report contemplates the HIV-encoded transactivator of transcription (Tat) protein, an early viral regulator, as a possible target (Chono et al., 2011a,b). Tat is produced early after HIV-1 infection and binds to the transactivation response (TAR) sequence, inducing the subsequent expression of other HIV-1 proteins. Thus, a Tat-dependent MazF expression system of a retroviral vector was constructed in which the mazF gene was inserted downstream the TAR sequence (Fig. 2a). Consequently, mazF was to be expressed when the HIV-1 viral Tat protein was produced and so to cleave the mRNA specifically at ACA codon in the infected cells. The mazF gene contains nine ACA sequences, which were engineered to avoid self-cleavage without altering the amino acid sequence and maintained its toxicity. On the other hand, the HIV RNA contains more than 240 ACA sequences, and thus the viral RNAs can hardly escape from the MazF attack. The experiment was conducted by transducing the recombinant plasmid into human T lymphoid line CEM-SS cells, which are highly susceptible to HIV infection. Strikingly, when the transduced cells were infected with HIV-1 IIIB, the replication of the infected virus was inhibited and the CD4 level was also not affected (as depicted in Fig. 2a). In addition, the level of MazF induced was not enough to cause serious cell damage and thus maintaining the normal cell growth. Similar results were observed when the Tat-dependent MazF system were investigated on rhesus macaque primary CD4+ T cells from monkeys that were infected with the chimerical virus SHIV 89.6P (Chono et al., 2011a,b).
Affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu, 9, 28006-Madrid, Spain.