Rational Design of Potent Peptide Inhibitors of the PD-1:PD-L1 Interaction for Cancer Immunotherapy

2021 ◽  
Author(s):  
Huawu Yin ◽  
Xiuman Zhou ◽  
Yen-Hua Huang ◽  
Gordon J. King ◽  
Brett M. Collins ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Rational Design ◽  
Peptide Inhibitors

scholarly journals Binding Ensembles of p53-MDM2 Peptide Inhibitors by Combining Bayesian Inference and Atomistic Simulations

Molecules ◽  
2021 ◽  
Vol 26 (1) ◽  
pp. 198
Author(s):  
Lijun Lang ◽  
Alberto Perez
Keyword(s):  
Bayesian Inference ◽  
Virtual Screening ◽  
Statistical Mechanics ◽  
Small Molecules ◽  
Rational Design ◽  
Driving Forces ◽  
Peptide Inhibitors ◽  
Atomistic Simulations ◽  
Binding Mechanism ◽  
Intrinsically Disordered

Designing peptide inhibitors of the p53-MDM2 interaction against cancer is of wide interest. Computational modeling and virtual screening are a well established step in the rational design of small molecules. But they face challenges for binding flexible peptide molecules that fold upon binding. We look at the ability of five different peptides, three of which are intrinsically disordered, to bind to MDM2 with a new Bayesian inference approach (MELD × MD). The method is able to capture the folding upon binding mechanism and differentiate binding preferences between the five peptides. Processing the ensembles with statistical mechanics tools depicts the most likely bound conformations and hints at differences in the binding mechanism. Finally, the study shows the importance of capturing two driving forces to binding in this system: the ability of peptides to adopt bound conformations (ΔGconformation) and the interaction between interface residues (ΔGinteraction).

scholarly journals Affinity maturation of the RLIP76 Ral binding domain to inform the design of stapled peptides targeting the Ral GTPases

2020 ◽  
pp. jbc.RA120.015735
Author(s):  
Catherine A Hurd ◽  
Paul Brear ◽  
Jefferson Revell ◽  
Sarah Ross ◽  
Helen R Mott ◽  
...  
Keyword(s):  
Rational Design ◽  
First Generation ◽  
Second Generation ◽  
Affinity Maturation ◽  
Peptide Inhibitors ◽  
Binding Domain ◽  
Stapled Peptides ◽  
Stapled Peptide ◽  
Protein Protein Interaction ◽  
Ral Gtpases

Ral GTPases have been implicated as critical drivers of cell growth and metastasis in numerous Ras-driven cancers. We have previously reported stapled peptides, based on the Ral effector RLIP76, that can disrupt Ral signaling. Stapled peptides are short peptides that are locked into their bioactive form using a synthetic brace. Here, using an affinity maturation of the RLIP76 Ral-binding domain, we identified several sequence substitutions that together improve binding to Ral proteins by more than 20-fold. Hits from the selection were rigorously analyzed to determine the contributions of individual residues and two 1.5 Å co-crystal structures of the tightest-binding mutants in complex with RalB revealed key interactions. Insights gained from this maturation were used to design second-generation stapled peptides based on RLIP76 that exhibited vastly improved selectivity for Ral GTPases when compared to the first-generation lead peptide. The binding of second-generation peptides to Ral proteins was quantified and the binding site of the lead peptide on RalB was determined by NMR. Stapled peptides successfully competed with multiple Ral-effector interactions in cellular lysates.  Our findings demonstrate how manipulation of a native binding partner can assist in the rational design of stapled peptide inhibitors targeting a protein–protein interaction.

Rational Design of Peptide Inhibitors of the Sarcoplasmic Reticulum Calcium Pump†

Biochemistry ◽  
2006 ◽  
Vol 45 (28) ◽  
pp. 8617-8627 ◽  
Author(s):  
Michael R. Afara ◽  
Catharine A. Trieber ◽  
John Paul Glaves ◽  
Howard S. Young
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Rational Design ◽  
Peptide Inhibitors ◽  
Calcium Pump ◽  
Sarcoplasmic Reticulum Calcium

scholarly journals 834 Rational design of recombinant modified vaccinia virus Ankara for cancer immunotherapy

2019 ◽  
Vol 139 (5) ◽  
pp. S144
Author(s):  
N. Yang ◽  
Y. Wang ◽  
S. Shuman ◽  
T. Merghoub ◽  
J.D. Wolchok ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Cancer Immunotherapy ◽  
Rational Design ◽  
Modified Vaccinia Virus Ankara

scholarly journals Systems glycobiology for discovering drug targets, biomarkers, and rational designs for glyco-immunotherapy

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Austin W. T. Chiang ◽  
Hratch M. Baghdassarian ◽  
Benjamin P. Kellman ◽  
Bokan Bao ◽  
James T. Sorrentino ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Drug Targets ◽  
Rational Design ◽  
Immune Cell ◽  
Current Knowledge ◽  
Clinical Findings ◽  
Immune Checkpoints ◽  
Great Promise ◽  
Oncology Research ◽  
Systemic Understanding

AbstractCancer immunotherapy has revolutionized treatment and led to an unprecedented wave of immuno-oncology research during the past two decades. In 2018, two pioneer immunotherapy innovators, Tasuku Honjo and James P. Allison, were awarded the Nobel Prize for their landmark cancer immunotherapy work regarding “cancer therapy by inhibition of negative immune regulation” –CTLA4 and PD-1 immune checkpoints. However, the challenge in the coming decade is to develop cancer immunotherapies that can more consistently treat various patients and cancer types. Overcoming this challenge requires a systemic understanding of the underlying interactions between immune cells, tumor cells, and immunotherapeutics. The role of aberrant glycosylation in this process, and how it influences tumor immunity and immunotherapy is beginning to emerge. Herein, we review current knowledge of miRNA-mediated regulatory mechanisms of glycosylation machinery, and how these carbohydrate moieties impact immune cell and tumor cell interactions. We discuss these insights in the context of clinical findings and provide an outlook on modulating the regulation of glycosylation to offer new therapeutic opportunities. Finally, in the coming age of systems glycobiology, we highlight how emerging technologies in systems glycobiology are enabling deeper insights into cancer immuno-oncology, helping identify novel drug targets and key biomarkers of cancer, and facilitating the rational design of glyco-immunotherapies. These hold great promise clinically in the immuno-oncology field.

scholarly journals Engineering dendritic cell vaccines to improve cancer immunotherapy

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Caleb R. Perez ◽  
Michele De Palma
Keyword(s):  
Cancer Immunotherapy ◽  
Rational Design ◽  
Adaptive Immune System ◽  
Tumour Microenvironment ◽  
Tumour Immunity ◽  
Dendritic Cell Vaccines ◽  
Dc Vaccines ◽  
Personalized Cancer

AbstractAt the interface between the innate and adaptive immune system, dendritic cells (DCs) play key roles in tumour immunity and hold a hitherto unrealized potential for cancer immunotherapy. Here we review the role of distinct DC subsets in the tumour microenvironment, with special emphasis on conventional type 1 DCs. Integrating new knowledge of DC biology and advancements in cell engineering, we provide a blueprint for the rational design of optimized DC vaccines for personalized cancer medicine.

Sign in / Sign up

Export Citation Format

Share Document