BIOMEDICAL APPLICATIONS OF “CLICK”-MODIFIED CYCLODEXTRINS - Click Chemistry in Glycoscience: New Developments and Strategies - page 278

O

N

O

S

N
N

N
H

Peptide

11

O

O

MeO

OMe

O

7

SCHEME 11.14 The design of “click” CD-based anthrax toxin antagonist. (Adapted from

ref. 39.)

of the lipophilic tails, the “click” clusters' self-assembling capability in complexing
with pDNA could be fine-tuned to facilitate the membrane-crossing and transfection
capabilities of the CD-pDNA complex [38].

11.3.4.2 -CD-based Anthrax Toxin Antagonist Anthrax is an acute infectious

disease caused by the bacterium Bacillus anthracis . Anthrax toxin, a three-protein
exotoxin secreted by virulent strains of Bacillus anthracis , plays a vital role in the
lethality of anthrax infection. Anthrax toxin is composed of two enzymes: lethal
factor (LF), edema factor (EF), and protective antigen (PA). PA is proteolytically
processed into fragments PA 63 that oligomerize to heptamers [PA 63 ] 7 . The heptamers
complex with LF and EF, and then translocated into the cytosol after endocytosis.
As a very smart approach, Joshi et al. used

β

-CD as a scaffold and “click”-grafted

seven PA inhibitory peptides to the -CD primary hydroxyl groups via PEG linker,

which produce an anthrax toxin antagonist with a nice spatial match to the [PA 63 ] 7
complex [39]. In the structural design, the selection of symmetric -CD as the

core scaffolding and the highly efficient “click” conjugation strategy are the key
to construct the molecule skeleton and achieve the inhibition effect (Scheme 11.14).
Due to the rational design, the “click” CD-based antagonist demonstrated a more than
100,000-fold increase in inhibitory activity than the monovalent peptide inhibitor.

11.3.4.3 Development of Delivery Carriers Using the Guest/Host Capability of
CDs Aliphatic polyesters, with fine biocompatibility and biodegradability, are
widely used in the bioengineering field (e.g., implant materials, prosthetics, surgical
sutures, bone screw) [40]. Aliphatic polyesters can be obtained via organic syn-
thetic method or fermentation. One limitation of the aliphatic polyesters, however, is
their lack of functionality, which makes it difficult for encapsulation and delivery of
water-soluble drugs and biologics. To address this issue, Jazkewitsch et al. introduce
pendent -CD to functionalized bacterial polyesters via “click” HDC reaction [41].

Two isomeric alkyne-functionalized ε -caprolactones, prepared by Baeyer-Villiger

oxidation, were copolymerized with -caprolactone using Sn(Oct) 2 and adipic acid as

co-initiators to give a pendent alkyne-functionalized poly(

ε

-caprolactone) (PCL) with
carboxylic acid at the chain termini, which was capped with 2,2-diphenylethanamine

ε