dc.contributor.author |
Ramanayake, R.M.T.M. |
|
dc.contributor.author |
Michigami, Masataka |
|
dc.contributor.author |
Ye, Zhengmao |
|
dc.contributor.author |
Uyeda, Atsuko |
|
dc.contributor.author |
Inoue, Norimitsu |
|
dc.contributor.author |
Sugiura, Kikuya |
|
dc.contributor.author |
Fujii, Ikuo |
|
dc.contributor.author |
Fujiwara, Daisuke |
|
dc.date.accessioned |
2023-02-09T06:33:19Z |
|
dc.date.available |
2023-02-09T06:33:19Z |
|
dc.date.issued |
2019-12-16 |
|
dc.identifier.citation |
Ramanayake Mudiyanselage, T. M., Michigami, M., Ye, Z., Uyeda, A., Inoue, N., Sugiura, K., ... & Fujiwara, D. (2019). An immune-stimulatory helix–loop–helix peptide: selective inhibition of CTLA-4–B7 interaction. ACS Chemical Biology, 15(2), 360-368. |
en_US |
dc.identifier.uri |
http://ir.lib.ruh.ac.lk/xmlui/handle/iruor/10956 |
|
dc.description.abstract |
Molecular-targeting peptides and mini-proteins
are promising alternatives to antibodies in a wide range of
applications in bioscience and medicine. We have developed a
helix−loop−helix (HLH) peptide as an alternative to
antibodies to inhibit specific protein interactions. Cytotoxic
T lymphocyte antigen-4 (CTLA-4) downregulates immune
responses of cytotoxic T-cells by interaction with B7-1, a co stimulatory molecule expressed on antigen presenting cells
(APCs). To induce immune stimulatory activity, we used directed evolution methods to generate a HLH peptide that binds to
CTLA-4, inhibiting the CTLA-4−B7-1 interaction and inducing immune stimulatory activity. Yeast-displayed libraries of HLH
peptides were constructed and screened against CTLA-4 and identified the binding peptide Y-2, which exhibits a moderate
affinity. The affinity of Y-2 was improved by in vitro affinity maturation to afford a stronger binder, ERY2-4. Peptide ERY2-4
specifically bound to CTLA-4 with a KD of 196.8 ± 2.3 nM, comparable to the affinity of the CTLA-4−B7-1 interaction.
Furthermore, ERY2-4 inhibited the CTLA-4−B7-1 interaction with an IC50 of 1.1 ± 0.03 μM and blocked the interaction
between CTLA-4 and dendritic cells (DCs) presenting B7 on their surface. Importantly, ERY2-4 showed no cross-reactivity
against CD28, suggesting it does not suppress T-cell activation. Finally, in a mixed lymphocyte reaction assay with DCs and T
cells, ERY2-4 enhanced an allogeneic lymphocyte response. Since CTLA-4 is a critical immune checkpoint for restricting the
cancer immune response, this inhibitory HLH peptide represents a new class of drug candidates for immunotherapy. |
en_US |
dc.language.iso |
en |
en_US |
dc.publisher |
ACS publcations |
en_US |
dc.subject |
CTLA-4 |
en_US |
dc.subject |
HLH peptide |
en_US |
dc.subject |
Biopolymers |
|
dc.subject |
Cells |
|
dc.subject |
Fungi |
|
dc.subject |
Immunology |
|
dc.subject |
Peptides and proteins |
|
dc.title |
An Immune-Stimulatory Helix–Loop–Helix Peptide: Selective Inhibition of CTLA-4–B7 Interaction |
en_US |
dc.type |
Article |
en_US |