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384 Cell-Penetrating Peptides: Processes and Applications
TABLE 18.1
Microbial Permeating Peptides
with Intracellular Targets
Name Putative intracellular target Ref.
Nicin Lipid II 72
PR-39 DNA and protein synthesis 8
Buforin 2 DNA/RNA 73
Histatins Mitochondria 74
Bac5 and Bac7 Respiration 75
ENAP-2 Serine proteases 76
depolarization of energized bacteria, or leakage of essential intracellular components.
30,41,42
18.3.2.2 Intracellular Target Inhibition
Early studies with antimicrobial peptides indicated that the mechanism of action
could involve binding to intracellular targets and many more examples of this mode
of action have recently been reported (Table 18.1). Several antimicrobial peptides,
including defensins, interact with heat shock protein (HSP) 70 and DNA. 43,44 These
peptides also can block general functions, including protein folding and protein
synthesis. For example, PR-39 is known to rapidly (within minutes) stop DNA and
protein synthesis in E. coli, apparently without causing cell lysis. 8 Indeed, several
examples of antimicrobial peptides with intracellular targets involve processes such
1,7,8,45- 47
as transcription, translation, protease activity, and mitochondrial function
(see also Table 18.1).
18.3.2.3 Dual Activities of Microbial Cell-Permeating Peptides
Many conventional antibiotics appear to kill cells via two or more mechanisms;
permeating peptides also can act in multiple ways to kill cells. The two applications
for cell-permeating peptides described below, cell permeabilization and cell delivery,
potentially can be combined for greater overall activities. Indeed, cell wall permeabilization
and toxic compound delivery could provide dual antimicrobial effects
for improved overall activity.
Also, it is possible to recombine domains from different antimicrobial peptides
to obtain new activity profiles, such as the cecropin–melittin hybrid and derivatives,
which appear to have two distinct activity domains. 48,49 The recombined peptide
shows greater overall activity and it appears that more than one cell-killing mechanism
is involved. The design rules for such domain shuffling experiments remain
uncertain, but there are opportunities to create more active hybrid peptides. For
example, in our attempts to develop antimicrobial peptide–PNA conjugates, one can
envision improved activity by invoking efficient cell wall permeabilization together
with efficient antisense effects against an essential gene. 6