Drug Targeting Organ-Specific Strategies

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Intermediaries for non peptide drugs
Mirror image phage display
Peptides with effector functions
Proteins with effector functions
(immunoneutralizing Abs)
De novo design & generation of proteins
with desired function & specificity
Cell ELISA
FACS
Western blot
Immunohistochemistry
In vitro and in vivo studies
10.2.2.2 Peptide Display
Scaffolds with functional residues
Affinity maturation
Engineering avidity & valency
Tailoring effector functions
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Figure 10.4. Application of phage display in drug and target discovery.
10.2 Phage Display Technology 259
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From 2D gels
From expression cDNA libraries
Select binders on complex antigens
Pathfinder
Cell selections
Tissue selections
In vivo selections
Western blot
Immunoprecipitation
Microsequencing
Expression cloning (cDNA libraries)
Since many proteins exert their biological activity through relatively small regions of their
folded surfaces, their interactions may in principle be reproduced by much smaller peptides
that retain these localized bioactive surfaces. Peptides can provide information about the
molecular interactions of protein binding sites [18], can be used as ligands for targeting purposes
[19], are useful intermediates in the development and design of non-peptide drugs [20],
and can act as small molecule drugs with biological activity [21]. Peptides are readily synthesized
and are characterized by rapid tissue penetration having potentially improved properties
for certain in vivo applications [22] (Figure 10.4).
The first reported random peptide libraries were constructed in 1990, and fused to pIII
[2–4]. These where followed by random libraries fused to pVIII [23]. The phage peptide libraries
are enriched on antigen, and clones analysed by sequencing to identify possible consensus
residues. Once consensus amino acid sequences are found among selected peptides,
the encoded peptides may be synthesized to confirm their specificity and determine affinity
for the target. The peptides themselves can be used as specific binding ligands in research or
diagnosis, for drug development, or they can form the starting point for the synthesis of
smaller bioactive molecules.