Chapter 3
In-Tether Chiral Center Induced Helical
Peptide Modulators Target
p53-MDM2/MDMX and Inhibit Tumor
Growth in Cancer Stem Cell
3.1 Introduction
Cancer is one of the most formidable diseases to combat. The cancer stem cell (CSC)
hypothesis provides a compelling cellular mechanism to account for the therapeutic
refractoriness and dormancy in cancer development. CSCs are a subset of stemlike cells that exhibit a unique spectrum of biologic, biochemical, and molecular
features and possess the ability to efficiently propagate the bulk of tumors [1–3]. Their
unlimited self-renewal and multipotency make CSCs more resistant to conventional
and targeted therapies [1, 4]. CSCs are believed to be the primary cause of tumor
recurrence and metastases [1, 2, 4, 5]. In clinical practice, CSCs need to be eradicated
for long-term disease-free survival [2, 5].
Conventional anticancer agents predominantly target tumor bulk populations
instead of CSCs. Increasing efforts have been directed toward the development of
CSC therapy, and new approaches such as nanomedicine have been employed for the
development of anti-CSC drugs [5–7]. In addition to self-renewal and pluripotency,
the high-level expression of the adenosine triphosphate–binding cassette (ABC)
transporters on CSC membranes enables CSC self-protection and constitutive drug
resistance against anticancer drugs [8, 9]. Drug resistance and issues in drug delivery
are the main obstacles in developing CSC therapy, and progress is compromised
by the lack of compounds with suitable biological functions and pharmacological
properties [6, 7] (Fig. 3.1).
Peptide stabilization is a technique for constraining short peptides into a fixed
secondary conformation, typically an α- helix [10, 11]. As protein-protein interactions (PPIs) were previously thought to be ‘undruggable’ by small molecules due to
their limited interacting surface area, stabilized peptides have become a promising
drug modality to target PPIs [12]. We precisely added a chiral center into the peptide
tether to constrain peptides into an α-helical conformation as shown in Fig. 3.2.
Compared to the S diastereomers, the R diastereomer peptide showed significantly
enhanced helical content, cellular uptake, and target binding affinity [13]. One major
© Springer Nature Singapore Pte Ltd. 2021
K. Hu, Development of In-Tether Carbon Chiral Center-Induced
Helical Peptide, Springer Theses,
https://doi.org/10.1007/978-981-33-6613-8_3
65
In-Tether Chiral Center Induced Helical
Peptide Modulators Target
p53-MDM2/MDMX and Inhibit Tumor
Growth in Cancer Stem Cell
3.1 Introduction
Cancer is one of the most formidable diseases to combat. The cancer stem cell (CSC)
hypothesis provides a compelling cellular mechanism to account for the therapeutic
refractoriness and dormancy in cancer development. CSCs are a subset of stemlike cells that exhibit a unique spectrum of biologic, biochemical, and molecular
features and possess the ability to efficiently propagate the bulk of tumors [1–3]. Their
unlimited self-renewal and multipotency make CSCs more resistant to conventional
and targeted therapies [1, 4]. CSCs are believed to be the primary cause of tumor
recurrence and metastases [1, 2, 4, 5]. In clinical practice, CSCs need to be eradicated
for long-term disease-free survival [2, 5].
Conventional anticancer agents predominantly target tumor bulk populations
instead of CSCs. Increasing efforts have been directed toward the development of
CSC therapy, and new approaches such as nanomedicine have been employed for the
development of anti-CSC drugs [5–7]. In addition to self-renewal and pluripotency,
the high-level expression of the adenosine triphosphate–binding cassette (ABC)
transporters on CSC membranes enables CSC self-protection and constitutive drug
resistance against anticancer drugs [8, 9]. Drug resistance and issues in drug delivery
are the main obstacles in developing CSC therapy, and progress is compromised
by the lack of compounds with suitable biological functions and pharmacological
properties [6, 7] (Fig. 3.1).
Peptide stabilization is a technique for constraining short peptides into a fixed
secondary conformation, typically an α- helix [10, 11]. As protein-protein interactions (PPIs) were previously thought to be ‘undruggable’ by small molecules due to
their limited interacting surface area, stabilized peptides have become a promising
drug modality to target PPIs [12]. We precisely added a chiral center into the peptide
tether to constrain peptides into an α-helical conformation as shown in Fig. 3.2.
Compared to the S diastereomers, the R diastereomer peptide showed significantly
enhanced helical content, cellular uptake, and target binding affinity [13]. One major
© Springer Nature Singapore Pte Ltd. 2021
K. Hu, Development of In-Tether Carbon Chiral Center-Induced
Helical Peptide, Springer Theses,
https://doi.org/10.1007/978-981-33-6613-8_3
65