4.2 Introduction to Prodrugs for Triple or Higher Action …
125
needs to consider both of these general specificity approaches. Controlling the interplay between selectivity, release mechanisms and nature of the released compounds
is important in the successful antibacterial application of prodrugs.
Sometimes useful general pointers towards achieving selective targeting of a
prodrug in one area can be obtained by looking at approaches used for tackling
these issues in other therapies. For example methods used for ligand targeting for
cancer (Rajendran et al. 2010; Srinivasarao et al. 2015) could be very useful in terms
of targeting antibacterial prodrugs with nuanced linker design and release mechanisms. The design of the anti-cancer prodrugs discussed by Srinivasarao et al. (2015)
is based on a ‘targeting ligand-spacer-cleavable bridge-warhead’ molecular structure
in which the targeting ligand component is crucial for site-directed delivery using the
ligand interaction with upregulated receptors on the cancer cell surface. Following
binding and endocytosis a number of bridge cleavage processes may occur, depending
on the nature of the linkage present, such as acid-catalysed hydrolysis in the acidic
lysosome or enzymatic cleavage of a peptide linker by lysosomal cathepsin B, or by
reduction of a disulfide linker by excess intracellular glutathione triggering subsequent intramolecular displacement of the active drug. From the antibacterial point
of view, incorporation of a cleavable disulfide bridge would be relevant as there is
no equivalent of endosomes/lysosomes in the bacterial cell. Also simplification of
the design would be desirable and might be possible based on a disulfide linker but
a suitable bacterial targeting ligand would still be vital. Glutathione plays important
roles in bacteria in maintaining appropriate cytoplasmic redox balance and through
blocking toxic compounds, amongst other roles. Bacteria have high concentrations
of GSH, and GSH transporters have been identified in bacteria.
Overall, from a prodrug multi-targeting design perspective, one would need to
consider a cleavable single compound which may be converted selectively in vivo
to one, two or more active compounds. These product compounds may each have
a single action or one or more of them may have multiple actions through other
target site interactions. One of the products might, for example, be a dual action
hybrid. Sometimes referred to as hybrid prodrugs, such hybrid active compound
release after enzymatic activation is well known in the literature (Domalaon et al.
2018). In another expression of this, one active compound may be released as a triple
action hybridic compound. For such potential triple action prodrugs similar general
structural motifs can be envisaged as noted for the triple action hybrid designs in
Chap. 3 (Sect. 3.3) but with the important incorporation of a cleavable group or
groups. In order to reduce potential negative off target effects in vivo, the cleavage
reaction should be triggered only when near or within the bacterium. Selectivity
is important here, and such triggers could include bacterially specific enzymes or
non-enzymatic mechanisms after selective accumulation.
125
needs to consider both of these general specificity approaches. Controlling the interplay between selectivity, release mechanisms and nature of the released compounds
is important in the successful antibacterial application of prodrugs.
Sometimes useful general pointers towards achieving selective targeting of a
prodrug in one area can be obtained by looking at approaches used for tackling
these issues in other therapies. For example methods used for ligand targeting for
cancer (Rajendran et al. 2010; Srinivasarao et al. 2015) could be very useful in terms
of targeting antibacterial prodrugs with nuanced linker design and release mechanisms. The design of the anti-cancer prodrugs discussed by Srinivasarao et al. (2015)
is based on a ‘targeting ligand-spacer-cleavable bridge-warhead’ molecular structure
in which the targeting ligand component is crucial for site-directed delivery using the
ligand interaction with upregulated receptors on the cancer cell surface. Following
binding and endocytosis a number of bridge cleavage processes may occur, depending
on the nature of the linkage present, such as acid-catalysed hydrolysis in the acidic
lysosome or enzymatic cleavage of a peptide linker by lysosomal cathepsin B, or by
reduction of a disulfide linker by excess intracellular glutathione triggering subsequent intramolecular displacement of the active drug. From the antibacterial point
of view, incorporation of a cleavable disulfide bridge would be relevant as there is
no equivalent of endosomes/lysosomes in the bacterial cell. Also simplification of
the design would be desirable and might be possible based on a disulfide linker but
a suitable bacterial targeting ligand would still be vital. Glutathione plays important
roles in bacteria in maintaining appropriate cytoplasmic redox balance and through
blocking toxic compounds, amongst other roles. Bacteria have high concentrations
of GSH, and GSH transporters have been identified in bacteria.
Overall, from a prodrug multi-targeting design perspective, one would need to
consider a cleavable single compound which may be converted selectively in vivo
to one, two or more active compounds. These product compounds may each have
a single action or one or more of them may have multiple actions through other
target site interactions. One of the products might, for example, be a dual action
hybrid. Sometimes referred to as hybrid prodrugs, such hybrid active compound
release after enzymatic activation is well known in the literature (Domalaon et al.
2018). In another expression of this, one active compound may be released as a triple
action hybridic compound. For such potential triple action prodrugs similar general
structural motifs can be envisaged as noted for the triple action hybrid designs in
Chap. 3 (Sect. 3.3) but with the important incorporation of a cleavable group or
groups. In order to reduce potential negative off target effects in vivo, the cleavage
reaction should be triggered only when near or within the bacterium. Selectivity
is important here, and such triggers could include bacterially specific enzymes or
non-enzymatic mechanisms after selective accumulation.