scholarly journals Structural Characterization of a Macrocyclic Peptide Modulator of the PD-1/PD-L1 Immune Checkpoint Axis

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4848
Author(s):  
Edyta Zyla ◽  
Bogdan Musielak ◽  
Tad A. Holak ◽  
Grzegorz Dubin
Keyword(s):  
Crystal Structure ◽  
Immune Checkpoint ◽  
Hydrophobic Interactions ◽  
Clinical Success ◽  
Binding Mode ◽  
Peptide Inhibitor ◽  
Binding Surface ◽  
Inhibitor Peptide ◽  
Macrocyclic Peptide

The clinical success of PD-1/PD-L1 immune checkpoint targeting antibodies in cancer is followed by efforts to develop small molecule inhibitors with better penetration into solid tumors and more favorable pharmacokinetics. Here we report the crystal structure of a macrocyclic peptide inhibitor (peptide 104) in complex with PD-L1. Our structure shows no indication of an unusual bifurcated binding mode demonstrated earlier for another peptide of the same family (peptide 101). The binding mode relies on extensive hydrophobic interactions at the center of the binding surface and an electrostatic patch at the side. An interesting sulfur/π interaction supports the macrocycle-receptor binding. Overall, our results allow a better understanding of forces guiding macrocycle affinity for PD-L1, providing a rationale for future structure-based inhibitor design and rational optimization.

scholarly journals Crystal structure of human RIOK2 bound to a specific inhibitor

Open Biology ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 190037 ◽  
Author(s):  
Jing Wang ◽  
Thibault Varin ◽  
Michal Vieth ◽  
Jonathan M. Elkins
Keyword(s):  
Crystal Structure ◽  
Binding Site ◽  
Hydrophobic Interactions ◽  
Specific Inhibitor ◽  
Binding Mode ◽  
Atp Binding ◽  
Active Site Residues ◽  
Atp Binding Site ◽  
Universal Family ◽  
Relationship Of

The RIO kinases (RIOKs) are a universal family of atypical kinases that are essential for assembly of the pre-40S ribosome complex. Here, we present the crystal structure of human RIO kinase 2 (RIOK2) bound to a specific inhibitor. This first crystal structure of an inhibitor-bound RIO kinase reveals the binding mode of the inhibitor and explains the structure–activity relationship of the inhibitor series. The inhibitor binds in the ATP-binding site and forms extensive hydrophobic interactions with residues at the entrance to the ATP-binding site. Analysis of the conservation of active site residues reveals the reasons for the specificity of the inhibitor for RIOK2 over RIOK1 and RIOK3, and it provides a template for inhibitor design against the human RIOK family.

Macrocyclic Peptide Inhibitor of PD‐1/PD‐L1 Immune Checkpoint

2020 ◽  
pp. 2000195
Author(s):  
Katarzyna Magiera‐Mularz ◽  
Katarzyna Kuska ◽  
Lukasz Skalniak ◽  
Przemyslaw Grudnik ◽  
Bogdan Musielak ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Peptide Inhibitor ◽  
Macrocyclic Peptide

scholarly journals Inhibitor Development against p7 Channel in Hepatitis C Virus

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1350
Author(s):  
Shukun Wei ◽  
Xiaoyou Hu ◽  
Lingyu Du ◽  
Linlin Zhao ◽  
Hongjuan Xue ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hydrophobic Interactions ◽  
Clinical Success ◽  
Antiviral Agents ◽  
Binding Mode ◽  
New Drugs ◽  
Mode Analysis ◽  
Inhibitor Development ◽  
Direct Acting Antiviral

Hepatitis C Virus (HCV) is the key cause of chronic and severe liver diseases. The recent direct-acting antiviral agents have shown the clinical success on HCV-related diseases, but the rapid HCV mutations of the virus highlight the sustaining necessity to develop new drugs. p7, the viroporin protein from HCV, has been sought after as a potential anti-HCV drug target. Several classes of compounds, such as amantadine and rimantadine have been testified for p7 inhibition. However, the efficacies of these compounds are not high. Here, we screened some novel p7 inhibitors with amantadine scaffold for the inhibitor development. The dissociation constant (Kd) of 42 ARD-series compounds were determined by nuclear magnetic resonance (NMR) titrations. The efficacies of the two best inhibitors, ARD87 and ARD112, were further confirmed using viral production assay. The binding mode analysis and binding stability for the strongest inhibitor were deciphered by molecular dynamics (MD) simulation. These ARD-series compounds together with 49 previously published compounds were further analyzed by molecular docking. Key pharmacophores were identified among the structure-similar compounds. Our studies suggest that different functional groups are highly correlated with the efficacy for inhibiting p7 of HCV, in which hydrophobic interactions are the dominant forces for the inhibition potency. Our findings provide guiding principles for designing higher affinity inhibitors of p7 as potential anti-HCV drug candidates.

scholarly journals Rational design of a potent macrocyclic peptide inhibitor targeting the PD-1/PD-L1 protein–protein interaction

RSC Advances ◽  
2021 ◽  
Vol 11 (38) ◽  
pp. 23270-23279
Author(s):  
Qi Miao ◽  
Wanheng Zhang ◽  
Kuojun Zhang ◽  
He Li ◽  
Jidong Zhu ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Protein Interaction ◽  
Rational Design ◽  
Peptide Inhibitor ◽  
Protein Protein Interaction ◽  
Comparable Activity ◽  
L1 Protein ◽  
Macrocyclic Peptide

The co-crystal structure and CADD-guided rational design of JMPDP-027 which has comparable activity to mAb in both in vitro and in vivo tests.

1672-P: Characterization of Immune Checkpoint Inhibitor–Mediated Hyperglycemia: Beyond Insulin-Dependent Diabetes

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1672-P
Author(s):  
AMANDA LEITER ◽  
EMILY CARROLL ◽  
DANIELLE C. BROOKS ◽  
JENNIFER BEN SHIMOL ◽  
ELLIOT EISENBERG ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Insulin Dependent Diabetes ◽  
Insulin Dependent

Ruthenium(II) Complexes Bearing Thioether-Appended α- Iminopyridine Ligands: Arene Precursors Permit Access to K2-N,N and K3-N,N,S Complexes

2019 ◽  
Author(s):  
Victoria A. Ternes ◽  
Hannah A. Morgan ◽  
Austin P. Lanquist ◽  
Michael P. Murray ◽  
Bradley Wile
Keyword(s):  
Crystal Structure ◽  
Solid State ◽  
Strong Field ◽  
Active Role ◽  
Binding Mode ◽  
Phenethyl Alcohol ◽  
Ru Complexes

Herein we report the preparation of a series of Ru(II) complexes featuring alpha-iminopyridine ligands bearing thioether functionality (NNS<sup>R</sup>, where R = Me, CH<sub>2</sub>Ph, Ph). Metallation using (<i>p</i> cymene)RuCl dimer permits access to (k<sup>2</sup>-N,N)Ru complexes in which the thioether moiety remains uncoordinated. In the presence of a strong field ligand such as acetonitrile or triphenylphosphine, the p-cymene moiety is displaced, and the ligand adopts a k<sup>3</sup>-N,N,S binding mode. These complexes are characterized using a combination of solution and solid state methods, including the crystal structure of [(NNS<sup>Me</sup>)Ru(NCMe)<sub>2</sub>Cl]Cl. The k<sup>2</sup>-N,N Ru(II) complexes are shown to serve as efficient precatalysts for the oxidation of sec-phenethyl alcohol at 5 mol% loadings, using a variety of external oxidants and solvents. The complex bearing an S-Ph donor was found to be the most active of those surveyed, suggesting that the thioether donor plays an active role in catalyst speciation for this transformation.

Crystal structure analysis of 4-R-phenyl-2,6-dimethyl-3,5-N-(dimethylcarbamoyl)-1,4-dihydropyridines [R=2-nitro (1), 4-methoxy (2) and 3,4-dichloro (3)]

1998 ◽  
Vol 213 (3) ◽  
Author(s):  
M. Bidya Sagar ◽  
K. Ravikumar ◽  
Y. S. Sadanandam
Keyword(s):  
Crystal Structure ◽  
Calcium Channel ◽  
Structure Analysis ◽  
Crystal Structure Analysis ◽  
Calcium Channel Antagonists

AbstractThe crystallographic characterization of the following three calcium channel antagonists is reported here: 2,6-dimethyl-3,5-dicarbamoyl-4-[2-nitro]-1,4-dihydropyridine (

scholarly journals Heteroleptic [Cu(P^P)(N^N)][PF6] Complexes: Effects of Isomer Switching from 2,2′-biquinoline to 1,1′-biisoquinoline

Crystals ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 185
Author(s):  
Nina Arnosti ◽  
Marco Meyer ◽  
Alessandro Prescimone ◽  
Edwin C. Constable ◽  
Catherine E. Housecroft
Keyword(s):  
Crystal Structure ◽  
Single Crystal ◽  
Nmr Spectra ◽  
Phenyl Ether ◽  
Quantum Yields ◽  
Dynamic Processes ◽  
Electrochemical Behaviors ◽  
Ambient Temperatures ◽  
Π Stacking

The preparation and characterization of [Cu(POP)(biq)][PF6] and [Cu(xantphos)(biq)][PF6] are reported (biq = 1,1′-biisoquinoline, POP = bis(2-(diphenylphosphanyl)phenyl)ether, and xantphos = (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane). The single crystal structure of [Cu(POP)(biq)][PF6] 0.5Et2O was determined and compared to that in three salts of [Cu(POP)(bq)]+ in which bq = 2,2′-biquinoline. The P–C–P angle is 114.456(19)o in [Cu(POP)(biq)]+ compared to a range of 118.29(3)–119.60(3)o [Cu(POP)(bq)]+. There is a change from an intra-POP PPh2-phenyl/(C6H4)2O-arene π-stacking in [Cu(POP)(biq)]+ to a π-stacking contact between the POP and bq ligands in [Cu(POP)(bq)]+. In solution and at ambient temperatures, the [Cu(POP)(biq)][PF6]+ and [Cu(xantphos)(biq)]+ cations undergo several concurrent dynamic processes, as evidenced in their multinuclear NMR spectra. The photophysical and electrochemical behaviors of the heteroleptic copper (I) complexes were investigated, and the effects of changing from bq to biq are described. Short Cu···O distances within the [Cu(POP)(biq)]+ and [Cu(xantphos)(biq)]+ cations may contribute to their very low photoluminescent quantum yields.

scholarly journals Recent Progress in Dendritic Cell-Based Cancer Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2495
Author(s):  
Kazuhiko Matsuo ◽  
Osamu Yoshie ◽  
Kosuke Kitahata ◽  
Momo Kamei ◽  
Yuta Hara ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Targeted Delivery ◽  
Cancer Vaccines ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Host Immune Responses ◽  
Near Future ◽  
Identification And Characterization

Cancer immunotherapy aims to treat cancer by enhancing cancer-specific host immune responses. Recently, cancer immunotherapy has been attracting much attention because of the successful clinical application of immune checkpoint inhibitors targeting the CTLA-4 and PD-1/PD-L1 pathways. However, although highly effective in some patients, immune checkpoint inhibitors are beneficial only in a limited fraction of patients, possibly because of the lack of enough cancer-specific immune cells, especially CD8+ cytotoxic T-lymphocytes (CTLs), in the host. On the other hand, studies on cancer vaccines, especially DC-based ones, have made significant progress in recent years. In particular, the identification and characterization of cross-presenting DCs have greatly advanced the strategy for the development of effective DC-based vaccines. In this review, we first summarize the surface markers and functional properties of the five major DC subsets. We then describe new approaches to induce antigen-specific CTLs by targeted delivery of antigens to cross-presenting DCs. In this context, the chemokine receptor XCR1 and its ligand XCL1, being selectively expressed by cross-presenting DCs and mainly produced by activated CD8+ T cells, respectively, provide highly promising molecular tools for this purpose. In the near future, CTL-inducing DC-based cancer vaccines may provide a new breakthrough in cancer immunotherapy alone or in combination with immune checkpoint inhibitors.

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