Biomedical Engineering Reference
In-Depth Information
characterized by a broad topological diversity, controlled again by ring size, transan-
nular interactions, and the presence of conformational restrictions [10].
8.2.3 Macrocycles in Drug Discovery
The role and potential of macrocycles in drug discovery has recently been the object
of several reviews [1a and c,13b,29]. Despite challenges inherent in such structures,
macrocycles have provided drugs or clinical lead compounds for most target classes,
including GPCRs, enzymes, DNA, and protein-protein interactions as well as oth-
erwise highly challenging targets [1c,29]. Such is the case for the HCV NS3/4A
protease, which presents a very shallow and featureless surface that escaped strate-
gies based on small molecules [30], or immunosuppressant drugs such as FK-506 or
rapamycin, macrolide antibiotics, and an antagonist of IL-17 [1a and c].
A common requirement of medicinal chemistry programs is the necessity to gener-
ate analogs with a sufficient diversity in order to optimize simultaneously the multiple
parameters associated with a drug candidate profile. As a result, access to synthetic
methods that enable diversity generation is a
sine qua non
component of a successful
medicinal chemistry program.
8.3 MACROCYCLIC PEPTIDES
Macrocyclic peptides have been known for decades and been initially isolated from
natural sources [31]. They are present in all kingdoms of life in sizes ranging from 10
to over 80 amino acids and possess a wide variety of natural and unnatural amino acid
composition, functioning generally as defense against predators [31]. Macrocycliza-
tion, predominantly head to tail or via disulfide bonds, plays a major role in conferring
on the molecule a high level of chemical and biological stability compared to its linear
congeners [32]. This favorable characteristic was recognized early by drug discovery
researchers, and hence has been the subject of numerous efforts to stabilize the topol-
ogy of drug candidates to endow them with added chemical and biological stability
[9e,11d and e,33]. Structure-permeation relationships and the improvement in the oral
bioavailability of peptides by way of macrocyclization has been studied extensively
by several groups [11b and c,34]. In particular, amide
N
-methylation, as exempli-
fied in cyclosporine, the influence of side-chain substituents, and lipophilicity on
permeation have all been scrutinized in several classes of macrocyclic peptides. The
assembly of macrocyclic peptides is also facilitated by four decades of automated pep-
tide synthesis and the ready availability of a broad diversity of natural and unnatural
amino acids. The following section reports selected examples of technologies which
have been developed for the production of large libraries of macrocyclic peptides.
8.3.1 Split-and-Pool Synthesis of Macrocyclic Peptides
The split-and-pool approach is an efficient avenue to generate large libraries (see
also Chapter 1). Pei and co-workers have recently reported the synthesis of a 10
7
-
membered library of macrocyclic peptides using a carefully engineered method
