Using extension-based mRNA display to design antibody-like proteinogenic peptides for human PD-L1.

Many peptide drugs rely on nonproteinogenic amino acids and chemical modifications for improved activity and proteolytic stability. However, these features also make drug production expensive and challenging to scale. Here, we engineered small, linear, proteinogenic peptides that bind human programmed death-ligand 1 (hPD-L1) with high affinity and stability using mRNA display affinity maturation.

A platform of ADAPTive scaffolds: development of CDR-H3 β-hairpin mimics into covalent inhibitors of the PD1/PDL1 immune checkpoint.

Aberrant and dysregulated protein-protein interactions (PPIs) drive a significant number of human diseases, which is why they represent a major class of targets in drug discovery. Although a number of high-affinity antibody-based drugs have emerged in this therapeutic space, the discovery of smaller PPI inhibitors is lagging far behind, underscoring the need for novel scaffold modalities. To bridge this gap, we introduce a biomimetic platform technology - adaptive design of antibody paratopes into therapeutics () - that enables the paratope-forming binding loops of antibodies to be crafted into large β-hairpin scaffolds ().

De Novo Synthesis and Structural Elucidation of CDR-H3 Loop Mimics.

The binding affinity of antibodies to specific antigens stems from a remarkably broad repertoire of hypervariable loops known as complementarity-determining regions (CDRs). While recognizing the pivotal role of the heavy-chain 3 CDRs (CDR-H3s) in maximizing antibody-antigen affinity and specificity, the key structural determinants responsible for their adaptability to diverse loop sequences, lengths, and noncanonical structures are hitherto unknown. To address this question, we achieved a de novo synthesis of bulged CDR-H3 mimics excised from their full antibody context.

Enantioselective Synthesis of (+)-Providencin and Its Unexpected Regioisomer via a Biomimetic Norrish-Yang Cyclization from (-)-Bipinnatin E.

A biomimetic semisynthesis of the diterpenoid (+)-providencin () and the unexpected novel C14 regioisomer was achieved by photoirradiation of the proposed biosynthetic cembranoid precursor (-)-bipinnatin E (). The absolute configuration assignments of and by correlation were established by X-ray analysis. A combination of NOESY data and photochemical reaction results revealed that both C2 and C14 positions of the macrocycle (-)- are suitable for hydrogen abstraction, thus affording an explanation to the mixture of cyclobutane photoproduct isomers obtained by a Norrish-Yang cyclization.

Tunable CH/π Interactions within a Tryptophan Zipper Motif to Stabilize the Fold of Long β-Hairpin Peptides.

The tryptophan zipper (Trpzip) is an iconic folding motif of β-hairpin peptides capitalizing on two pairs of cross-strand tryptophans, each stabilized by an aromatic-aromatic stacking in an edge-to-face (EF) geometry. Yet, the origins and the contribution of this EF packing to the unique Trpzip stability remain poorly understood. To address this question of structure-stability relationship, a library of Trpzip hairpins was developed by incorporating readily accessible nonproteinogenic tryptophans of varying electron densities.

Passive Membrane Permeability of Sizable Acyclic β-Hairpin Peptides.

The recent shift toward increasingly larger drug modalities has created a significant demand for novel classes of compounds with high membrane permeability that can inhibit intracellular protein-protein interactions (PPIs). While major advances have been made in the design of cell-permeable helices, stapled β-sheets, and cyclic peptides, the development of large acyclic β-hairpins lags far behind. Therefore, we investigated a series of 26 β-hairpins (MW > 1.

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 Å ) across several distant epitopes of PD1.

Folding in Place: Design of β-Strap Motifs to Stabilize the Folding of Hairpins with Long Loops.

Despite their pivotal role in defining antibody affinity and protein function, β-hairpins harboring long noncanonical loops remain synthetically challenging because of the large entropic penalty associated with their conformational folding. Little is known about the contribution and impact of stabilizing motifs on the folding of β-hairpins with loops of variable length and plasticity. Here, we report a design of minimalist β-straps (strap = strand + cap) that offset the entropic cost of long-loop folding.

Role of Macrocyclic Conformational Steering in a Kinetic Route toward Bielschowskysin.

Macrocyclic furanobutenolide-derived cembranoids (FBCs) are the biosynthetic precursors to a wide variety of highly congested and oxygenated polycyclic (nor)diterpenes (e.g. plumarellide, verrillin, and bielschowskysin).

Structure-Property Relationship Study of -(Hydroxy)Peptides for the Design of Self-Assembled Parallel β-Sheets.

The design of novel and functional biomimetic foldamers remains a major challenge in creating mimics of native protein structures. Herein, we report the stabilization of a remarkably short β-sheet by incorporating -(hydroxy)glycine (Hyg) residues into the backbone of peptides. These peptide-peptoid hybrids form unique parallel β-sheet structures by self-assembly upon hydrogenation.

A Broad Substrate Scope of Aza-Friedel-Crafts Alkylation for the Synthesis of Quaternary α-Amino Esters.

A versatile synthetic protocol of aza-Friedel-Crafts alkylation has been developed for the synthesis of quaternary α-amino esters. This operationally simple alkylation proceeds under ambient conditions with high efficiency, regioselectivity, and an exceptionally broad scope of arene nucleophiles. A key feature of this alkylation is the role associated with the silver(I) salt counteranions liberated during the reaction.

Synthesis and Reactivity of α-Haloglycine Esters: Hyperconjugation in Action.

A general and efficient synthesis of α-haloglycine esters from commercially available feedstock chemicals, in a single step, is reported. The reactivity of these α-haloglycine esters with various nucleophiles was studied as surrogates of α-iminoesters upon activation with hydrogen-bond donor catalysts. DFT calculations on the α-haloglycine structures (X = F, Cl, Br) accompanied by an X-ray characterization of the α-bromoglycine ester support the existence of a "generalized" anomeric effect created by hyperconjugation.

Intercepted-Knoevenagel condensation for the synthesis of unsymmetrical fused-tricyclic 4-pyrans.

4-Pyrans (4-Pys) and 1,4-dihydropyridines (1,4-DHPs) are important classes of heterocyclic scaffolds in medicinal chemistry. Herein, an indium(III)-catalyzed one-pot domino reaction for the synthesis of highly functionalized 4-Pys, and a model of 1,4-DHP is reported. This alternative approach to the challenging Hantzsch 4-component reaction enables the synthesis of fused-tricyclic heterocycles, and the mechanistic studies underline the importance of an intercepted-Knoevenagel adduct to achieve higher chemoselectivity towards these types of unsymmetrical heterocycles.

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.

Enantioselective Synthesis of α-Allyl Amino Esters via Hydrogen-Bond-Donor Catalysis.

We report a chiral-squaramide-catalyzed enantio- and diastereoselective synthesis of α-allyl amino esters. The optimized protocol provides access to -carbamoyl-protected amino esters via nucleophilic allylation of readily accessible α-chloro glycinates. A variety of useful α-allyl amino esters were prepared, including crotylated products bearing vicinal stereocenters that are inaccessible through enolate alkylation, with high enantioselectivity (up to 97% ee) and diastereoselectivity (>10:1).

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.

Synthesis of α-Arylated Cycloalkanones from Congested Trisubstituted Spiro-epoxides: Application of the House-Meinwald Rearrangement for Ring Expansion.

A three-step sequence for the synthesis of α-arylated cyclohexanones and the most challenging cycloheptanones is reported. First, an efficient one-pot synthesis of β,β'-disubstituted benzylidene cycloalkanes (styrenes) using the palladium-catalyzed Barluenga reaction from readily available feedstock chemicals is described. Furthermore, an epoxidation followed by the House-Meinwald rearrangement (HMR) of spiro-epoxides is reported to produce a number of α-arylated cycloalkanones upon ring expansion.

A Kinetic Dearomatization Strategy for an Expedient Biomimetic Route to the Bielschowskysin Skeleton.

Bielschowskysin (1), the flagship of the furanocembranoid diterpene family, has attracted attention from chemists owing to its intriguing and daunting polycyclic architecture and medicinal potential against lung cancer. The high level of functionalization of 1 poses a considerable challenge to synthesis. Herein, a stereoselective furan dearomatization strategy of furanocembranoids was achieved via the intermediacy of chlorohydrins.

In Situ-Generated Glycinyl Chloroaminals for a One-Pot Synthesis of Non-proteinogenic α-Amino Esters.

An acetyl chloride-mediated cascade transformation involving a primary carbamate, ethyl glyoxylate, and various types of nucleophiles is reported for the synthesis of orthogonally protected α-amino esters. These reactions proceeded rapidly to afford the pivotal α-chloroglycine intermediate in excellent yields, which can be directly functionalized in situ with various types of nucleophiles. A mild and unique AcOH(cat.

Synthesis of Briarane Diterpenoids: Biomimetic Transannular Oxa-6Ï€ electrocyclization Induced by a UVA/UVC Photoswitch.

A biomimetic synthesis of briareolate ester B (3) from briareolate ester L (1) via the intermediate briareolate ester G (2) has been achieved through a unique transannular oxa-6π electrocyclization induced by UVA light. UVC irradiation of 3 triggered a rapid retro-6π electrocyclization to establish an unprecedented photochromic switch. In the ground state, reaction of 1 led to the formation of a polycyclic γ-spiroketal γ-lactone 5, architecturally related to the ether-bridged cembranoids of the cladiellin class.

Multicomponent assembly of 4-aza-podophyllotoxins: A fast entry to highly selective and potent anti-leukemic agents.

The aim of this study was the synthesis and lead structure selection of a best anti-leukemic agent from a library of aza-podophyllotoxin analogues (APTs). To this end, we report a scalable, modified multicomponent reaction using a "sacrificial" aniline partner as a more general route to rapidly construct the pivotal library of 50 APT analogues. Our preliminary structure activity relationship studies for anti-leukemic activity also address the innate toxicity of these compounds against non-malignant cells.

Asymmetric Mannich synthesis of α-amino esters by anion-binding catalysis.

We report a scalable, one-pot Mannich route to enantioenriched α-amino esters by direct reaction of α-chloroglycine ester as a practical imino ester surrogate. The reaction is promoted by a chiral aminothiourea, which is proposed to operate cooperatively by generating an iminium ion by chloride abstraction and an enolate by deprotonation, followed by highly stereoselective C-C bond formation between both reactive intermediates associated non-covalently within the catalyst framework.

Autocatalytic one pot orchestration for the synthesis of α-arylated, α-amino esters.

A novel acetyl chloride-mediated cascade transformation involving three components (benzyl carbamate, ethyl glyoxylate and arene nucleophiles) is reported. Aryl orthogonally protected α-amino acids are obtained in a one pot cascade, using a mild AcOH-AcCl system, via a critical autocatalytic dehydration-activation step ensuring an original and efficient Friedel-Crafts orchestration.

Double annulative cascade of tryptophan-containing peptides triggered by selectfluor.

A common dearomative strategy toward the kapakahines B/F and chaetominine natural products is reported. The proposed biomimetic strategy generates the tetracyclic α-carboline core in a single step, featuring a selectfluor-mediated dearomatization of preactivated N-Phth-Trp-Xaa-OR dipeptides at the C-terminus. The pivotal cascade includes a double annulation and the formation of three carbon-heteroatom bonds while gaining, for the first time, some insight on the diastereoselectivity outcome during the formation of the α-carboline fragment.

Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state.

The ribosome is centrally situated to sense metabolic states, but whether its activity, in turn, coherently rewires transcriptional responses is unknown. Here, through integrated chemical-genetic analyses, we found that a dominant transcriptional effect of blocking protein translation in cancer cells was inactivation of heat shock factor 1 (HSF1), a multifaceted transcriptional regulator of the heat-shock response and many other cellular processes essential for anabolic metabolism, cellular proliferation, and tumorigenesis. These analyses linked translational flux to the regulation of HSF1 transcriptional activity and to the modulation of energy metabolism.