Introduction
Peptides consist of 5-50 amino acids and have a molecular weight between
small molecules (500 Da) and antibodies (5000 Da)1, 2.
Unlike small molecules, they are also not susceptible to degradation in
the human body, and thus display longer tumor retention. Moreover,
peptides can be rationally designed based on the sequence of protein
targets or interaction binding sites, affording them higher specificity
and selectivity than small molecules. Compared to antibodies, the
smaller peptides have a shorter clearance time from healthy organs and
can be easily synthesized or chemically modified 3-6.
Therefore, peptides are emerging as efficient treatment modalities for
various diseases. They can be used as carriers for delivery of drugs to
disease-associated targets7. For example,
peptide-conjugated radionuclides are an efficient approach to delivering
local radiation to cancer targets and killing tumor
cells1, 8, 9. Cell-penetrating peptides are potential
carriers to send drugs across the blood-brain barrier into the brain.
Many peptides also show remarkable therapeutic efficacy, which could
also serve as a treatment modality10-12. Multiple
peptide-based drugs have been approved for clinical practice,
highlighting the need for further studies to develop more efficient
peptide drugs 6.
However, one of the largest gaps between basic research and clinical
application for screening peptide drugs as potential treatments derives
from the differences between existing preclinical models and
human13. The animal models and two-dimensional (2D)
cell lines cannot fully preserve characteristics of in vivo human cells,
contributing to the high failure rate of tested drugs in phase I–III
clinical trials, resulting in a significant waste of medical
resources14-16. The emergence of organoids provides
new insights into establishing a novel model system. Organoids are
three-dimensional (3D) multicellular constructs primarily generated from
pluripotent stem cells (PSCs) and adult stem cells (ASCs) through
self-organization and self-renewal13. They can
recapitulate the structural and functional features of their in vivo
counterparts17-19. Compared to time-consuming animal
models, organoids are easy to establish and
manipulate20-29. Importantly, they can be used to
study the mechanism of human diseases that are difficult to model in
animals25, 30, 31. Although human cells can be
maintained under two-dimensional conditions, they almost lose the
features of native organs due to the lack of a similar
microenvironment24, 32, 33. The three-dimensional
cultured organoids exhibit near-physiologic cellular composition and
behaviors, and maintain genome stability even after long-term
expansion18. These advantages make organoids suitable
preclinical models for high-throughput drug screening, which help to
exclude a series of resistant drugs in the human body, which thus
provides an effective approach to develop new drugs (Figure
1)34-37.
A wide range of studies have focused on evaluating the feasibility and
utility of organoids in small molecular drug screens, from investigating
drug response to establishing organoid-based high-throughput screening
platforms13, 38, 39. Although there are several
applications of organoids in studying peptide-based drugs, a
high-throughput organoid-based platform for screening peptides has not
been reported. Given the advantages of peptides, we believe the organoid
models will facilitate the development and clinical application of
peptide-conjugated drugs and therapeutic peptides.
This review discusses the
advantages of organoids in peptide drug screens and how we learn from
organoid-based small molecular drug screening platforms based on the
feature of peptides. In the first part, the typical studies involving
small molecular drug application in organoid models are introduced, and
an overview of the methodology and theory of these studies are provided.
The second part discusses the recent attempts to introduce peptide drugs
in organoid models and presents the perspective and challenges of
organoid-based high throughput peptide screening platforms.