الفهرس 
صفحة العنوانOnly 14 pages are availabe for public view
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Abstract
Synthesis and screening of novel libraries of cyclic peptides as anticancer
agents
Protein-protein interactions (PPls) control several cellular signaling pathways and involved in
various human diseases. Moreover, malfunction or mutation in such interactions can cause cancer.
The flat large interface between the binary proteins challenges targeting PPls with small
molecules. This work aims to interrupt different PPls involved in human cancer by cyclic peptides
through three different strategies.
Part 1 of the thesis targets Pin I protein which catalyzes the cis/trans isomerization around the
prolyl bond of many phosphorylated proteins. Also, Pin 1 controls the stability and activity of many
transcriptional factors involved in the cell proliferation and growth. Pin \ has been targeted by
cyclic peptides as their high structural rigidity increase their proteolytic stability. However, the
poor cellular permeability of cyclic peptides decreases the intracellular inhibition of Pin I. In this
section, we’ have been able to design cycloheptapeptides (peptides 1-12) and test their binding
affinity to Pin 1, cellular uptake efficiency and their ability to inhibit the cancerous cells viability.
Peptide 9 was the most potent cycloheptapeptide as it possesses Pin 1 inhibitory activity with an
lC50 value of 245 nM. Peptide 9 can cross the cell membrane efficiently, and inhibits Pin 1
intracellularly as shown by western blotting and MTT in vitro assays.
Part 2 aims at the challenging inhibition of Ras protein which was declared ”undruggable” for
many years due to the lack of any major pockets on the Ras surface. A library of approximately
6.37x I 05 bicyclic peptides (peptide-17-library) was synthesized and screened against G 12V
mutated KRas; G 12V is considered the most common mutation of Ras proteins involved in cancer.
The most potent peptides structures were identified by partial Edman degradation (PEO),
synthesized on a large scale and thoroughly tested in vitro by different biological assays. Peptide
24 displayed the most potent inhibitory activity with an IC50 value of 500 nM by preventing the
interaction of KRas(G 12V) with its partner protein (Raf). Modification of peptide 24 gave rise to
peptides 50-58. Peptide 55 was the most potent analog as it shows two folds improved inhibition
ofKRas(G 12V)-Raf interaction relative to peptide 24 with IC50 value of 247 nM.