Exploiting the Innate Plasticity of the Programmed Cell Death-1 (PD1) Receptor to Design Pembrolizumab H3 Loop Mimics.

Checkpoint blockade of the immunoreceptor programmed cell death-1 (PD1) with its ligand-1 (PDL1) by monoclonal antibodies such as pembrolizumab provided compelling clinical results in various cancer types, yet the molecular mechanism by which this drug blocks the PD1/PDL1 interface remains unclear. To address this question, we examined the conformational motion of PD1 associated with the binding of pembrolizumab. Our results revealed that the innate plasticity of both C'D and FG loops is crucial to form a deep binding groove (371 Å3 ) across several distant epitopes of PD1. This analysis ultimately provided a rational-design to create pembrolizumab H3 loop mimics [RDYRFDMGFD] into ß-hairpin scaffolds. As a result, a 20-residue long ß-hairpin peptide 1 e was identified as a first-in-class potent PD1-inhibitor (EC50 of 0.29 µM; Ki of 41 nM).

Total synthesis of (±)-fumimycin and analogues for biological evaluation as peptide deformylase inhibitors.

A concise 7-step total synthesis of (±)-fumimycin in 11.6 % overall yield is reported. An acid-catalyzed intramolecular aza-Friedel-Crafts cyclization was developed to construct the benzofuranone skeleton of the natural product bearing an α,α-disubstituted amino acid moiety in a single step. Regioselective chlorination followed by a Suzuki-Miyaura cross-coupling rapidly enabled the preparation of a library of analogues which were evaluated against peptide deformylase for antibacterial activity.

Nivolumab to pembrolizumab switch induced a durable melanoma response: A case report.

RATIONALE: While checkpoint inhibitors have revolutionized the treatment of melanoma, it is not known whether switching from one monoclonal antibody drug to another one would be justified in the case of a treatment failure. Herein, we report a case illustrating a durable response to pembrolizumab after a failure with nivolumab. PATIENT CONCERNS: A 76-year-old white male noticed an enlarging papular lesion on his neck. DIAGNOSIS: Malignant melanoma. INTERVENTIONS: The patient underwent surgery in December 2013 and was found to have a B-Rapidly Accelerated Fibrosarcoma (BRAF) V600E mutated melanoma. Treatment with BRAF and MAPK/Erk kinase (MEK) inhibitors along with radiation was initiated. After 1 year, the disease progressed, and the treatment was switched to the cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody, ipilimumab. As the tumor did not respond, the treatment was changed to programmed cell death receptor-1 (PD-1) blockers: nivolumab followed by pembrolizumab. Since the initial diagnosis, the tumor response was monitored by computed tomography (CT) scans. Immunohistochemistry (IHC) was also used for the assessment of programmed death ligand 1 PD-L1) expression in the neck, lung, and spleen lesions. OUTCOMES: The patient had an initial mixed response to nivolumab, but the disease ultimately progressed as evidenced by new metastases to the spleen, thus the treatment was switched to pembrolizumab. After 46 cycles of treatment, all sites of metastases disappeared, including a substantial shrinkage of the splenic metastasis. To gain understanding about the pharmacological differences between nivolumab and pembrolizumab, the PD-1-ligands interactions and conformational dynamics responsible for the PD-1/PD-L1 checkpoint blockade were investigated. The higher affinity of pembrolizumab might likely arise from a unique and large patch of interactions engaging the C'D loop of PD-1, thus forcing an important motion across the PD-1 immunoreceptor. LESSONS: In this case report, we described the tolerance and response of a melanoma patient to a sequence of various agents, including ipilimumab, nivolumab, and pembrolizumab. To the best of our knowledge, this is the first clinical report highlighting differences between PD-1 blockers, as shown by the unexpected and durable response of the tumor to pembrolizumab, after a treatment failure with nivolumab.

Multifaceted Study on a Cytochalasin Scaffold: Lessons on Reactivity, Multidentate Catalysis, and Anticancer Properties.

An intramolecular Diels-Alder (IMDA) reaction efficiently accelerated by Schreiner's thiourea is reported, to build a functionalized cytochalasin scaffold (periconiasin series) for biological purposes. DFT calculation highlighted a unique multidentate cooperative hydrogen bonding in this catalysis. The deprotection end game afforded a collection of diverse structures and showed the peculiar reactivity of the Diels-Alder cycloadducts upon functionalization. Biological studies revealed strong cytotoxicity of a few compounds on breast cancer cell lines while actin polymerization is preserved.

First Total Synthesis, Structure Revision, and Natural History of the Smallest Cytochalasin: (+)-Periconiasin G.

The total synthesis of the smallest cytochalasin isolated so far, periconiasin G, which bears a seven-membered ring in lieu of the usual macrocycle, has been performed from both enantiomers of citronellal, relying on an intramolecular Diels-Alder reaction in favor of the natural endo stereochemistry. We show that, among the four synthesized stereoisomers, including the exo isomers, the one matching the NMR data of the natural product was not that assigned in the original report, imposing structure revision. The natural product, previously isolated from a plant-mutualistic fungus, was biologically investigated taking into account its natural history, showing significant effects against the phytopathogenic fungus Botrytis cinerea and thus opening new opportunities in combating this pest.

3-Acylated tetramic and tetronic acids as natural metal binders: myth or reality?

Covering: up to 20153-Acylated tetramic and tetronic acids are characterized by a low pKa and are likely to be deprotonated under physiological conditions. In addition, their structure makes them excellent chelators of metallic cations. We will discuss the significance of these chemical properties with regard to the biological properties and mechanisms of action of these compounds, highlighting the importance of considering them as salts or chelates for biological purposes, rather than acids.