The coming of age of cyclic peptide drugs: an update on discovery technologies

ABSTRACT

Introduction

Cyclic peptides are an established class of pharmaceuticals, with the ability to bind to a broader range of protein targets than traditional small molecules while also being capable of oral availability and cell penetration. Historically, cyclic peptide drugs have been discovered almost exclusively through natural product mining approaches; however, the last two decades have seen the development of display screening approaches capable of rapidly identifying de novo (i.e. not natural product derived) cyclic peptide ligands to targets of interest.

Areas covered

In this review, the authors describe the current clinical landscape for cyclic peptide pharmaceuticals. This article focuses on the discovery approaches that have led to the development of different classes of molecules and how the development of newer technologies, particularly phage and mRNA display, has broadened the clinical applicability of such molecules.

Expert opinion

The field of de novo cyclic peptide drug discovery is reaching maturity, with the first drugs identified through display screening approaches reaching the market in recent years. Many more are in clinical trials; however, significant technical challenges remain. Technological improvements will be required over the coming years to facilitate the identification of membrane permeable cyclic peptides capable of oral availability and targeting intracellular proteins.

KEYWORDS:

• Macrocycle
• peptide
• display screening
• drug discovery

Article highlights

• Macrocyclic peptides are a useful class of pharmaceuticals with advantages over both traditional small molecules and monoclonal antibodies.

• They have historically been discovered through natural product panning, and or rational design approaches, but this has limited their application to relatively few disease-related targets.

• Screening technologies such phage and mRNA display have broadened the scope of macrocyclic peptide pharmaceuticals leading to the development of new drugs against diverse targets.

• The combination of such techniques with genetic code reprogramming has further broadened the utility of macrocyclic peptides by allowing the discovery of orally available molecules capable of intracellular targeting.

• The coming decade is highly likely to see the approval of numerous entirely novel macrocyclic peptide-based drugs.

List of abbreviations

AARS	=	Aminoacyl-tRNA synthetase
ATP	=	Adenosine triphosphate
CD38	=	Cluster of differentiation 38
cDNA	=	Complementary DNA
Da	=	Daltons
DNA	=	Deoxyribonucleic acid
EphaA2	=	Ephrin type A receptor 2
F%	=	Bioavailability
HCV	=	Hepatitis C virus
HDAC	=	Histone deacetylase
IC50	=	Half maximal inhibitory concentration
IgG	=	Immunoglobulin G
IL23R	=	Interleukin 23 receptor
Ki	=	Inhibitory constant
mAb	=	Monoclonal antibodies
MM	=	Multiple myeloma
MMP14	=	Matrix metalloproteinase 14
mRNA	=	Messenger RNA
ncAA	=	Non-canonical amino acid
NP	=	Natural product
PCSK9	=	Proprotein Convertase Subtilisin/Kexin Type 9
PDL1	=	Programmed cell death ligand 1 protein
PET	=	Positron emission tomography
RNA	=	Ribonucleic acid
RT-PCR	=	Reverse transcription-polymerase chain reaction
SARS-CoV-2	=	Severe acute respiratory syndrome coronavirus 2
tRNA	=	Transfer ribonucleic acid

Declaration of interest

S You, T Passioura, and G McIntyre are all employees of Insamo South Pty Ltd, while T Passioura and G McIntyre are also directors of both Insamo South Pty Ltd and Insamo Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are funded by the University of Sydney and Insamo South Pty Ltd.