Biomedical Engineering Reference
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FIGURE 8.5 -Hairpin mimetic possessing the L-Pro-D-Pro dipeptide motif: structure of
the CXCR4 agonist precursor POL3026 .
features 14-membered rings formed by amino acids selected to bind RNA targets,
such as those found in naturally occurring macrocyclic antibiotics targeting bacterial
ribosomal RNA. This library led to the identification of several compounds able to
inhibit translation. However, none of the actives identified demonstrated minimal
inhibitory concentrations against Escherichia coli or Staphylococcus aureus strains
at 100
M [60].
-Hairpin mimics have been designed and synthesized using larger macrocycles,
following a principle reminiscent of the secondary structure imposed to gramicidin
SbytwoD-Phe-L-Pro residues at the turn regions (Figure 8.5) [61a-c]. Stabilization
of the
-sheet secondary structure has been achieved successfully via the use of the
L-Pro-D-Pro dipeptide, which imposes a type II
-turn which serves as a template
linking the N and C terminals of a linear peptide chain, stabilizing two antiparallel
strands linked together by intramolecular hydrogen bonds. This technology [62]
has led to several applications, such as mimics of the TAT bound to HIV-1 RNA,
protease inhibitors, and cationic host defense peptides [63]. So far it has delivered
two clinical candidates. POL6326 is a competitive inhibitor of CXCR4 currently in
clinical phase II for hematopoietic stem cell transplant and in phase I for cancer and
tissue repair (see Figure 8.5 for the structure of CXCR4 agonist precursor POL3026 )
[64]. POL7080 , an antibiotic efficacious against Pseudomonas infections, is in phase
I clinical development. Additional congeners from the same technology include
POL6014 , a competitive inhibitor of human neutrophil elastase with potential against
chronic obstructive pulmonary disease [61c].
Stabilization of helical secondary structure has also been achieved via the side-
chain to side-chain cyclization of residues located one helix turn apart, in an approach
called “stapled peptides,” which have been applied to multiple systems (see for exam-
ple [61d-h]). The latter has already delivered a first clinical candidate, ALRN-5281,
a long-acting growth hormone-releasing hormone agonist for the treatment of con-
ditions such as growth hormone deficiency and HIV-related lipodystrophy [61d-h].
8.4.2 Diversity-Oriented Synthesis of Macrocyclic Peptidomimetics
Spring and co-workers reported the synthesis of macrocyclic peptidomimetics pos-
sessing general formulas 45 and 46 (Scheme 8.8) [65]. Both scaffolds are read-
ily diversified, which is highly desirable for the optimization of potentially active
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