Titia

Publication date: 15 September 2022

Source: Cell, Volume 185, Issue 19

Author(s): Gaurav Bhardwaj, Jacob O’Connor, Stephen Rettie, Yen-Hua Huang, Theresa A. Ramelot, Vikram Khipple Mulligan, Gizem Gokce Alpkilic, Jonathan Palmer, Asim K. Bera, Matthew J. Bick, Maddalena Di Piazza, Xinting Li, Parisa Hosseinzadeh, Timothy W. Craven, Roberto Tejero, Anna Lauko, Ryan Choi, Calina Glynn, Linlin Dong, Robert Griffin

Using machine learning models trained with bioactive peptides from DBAASP, we designed new non-hemolytic anticancer peptides (ACPs). The subsequently selected hit-compounds A1 and B1 showed IC₅₀ activities with low micromolar range against several cancer cell lines, having adopted amphiphilic α-helical conformations. Further biological evaluations revealed membranolytic and mitochondria targeting properties of selected anticancer peptides.

Abstract

Most antimicrobial peptides (AMPs) and anticancer peptides (ACPs) fold into membrane disruptive cationic amphiphilic α-helices, many of which are however also unpredictably hemolytic and toxic. Here we exploited the ability of recurrent neural networks (RNN) to distinguish active from inactive and non-hemolytic from hemolytic AMPs and ACPs to discover new non-hemolytic ACPs. Our discovery pipeline involved: 1) sequence generation using either a generative RNN or a genetic algorithm, 2) RNN classification for activity and hemolysis, 3) selection for sequence novelty, helicity and amphiphilicity, and 4) synthesis and testing. Experimental evaluation of thirty-three peptides resulted in eleven active ACPs, four of which were non-hemolytic, with properties resembling those of the natural ACP lasioglossin III. These experiments show the first example of direct machine learning guided discovery of non-hemolytic ACPs.

Nature Chemical Biology, Published online: 14 July 2022; doi:10.1038/s41589-022-01076-6

Synlett
DOI: 10.1055/s-0040-1719931

We report an amino acid salt-catalyzed direct desymmetrization of 3-substituted cyclobutanones through a direct aldol reaction under mild reaction conditions. The developed method provides an array of highly functionalized cyclobutanones bearing three contiguous stereogenic centers in high yields and stereoselectivities with varied functional-group compatibility. Furthermore, the obtained adducts can be smoothly converted into polyfunctional 1,4-butyrolactones with maintained enantioselectivity.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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Does affinity come from constraint ? The thermodynamic and structural analysis of a series of constrained peptide ligands and unconstrained analogues accurately describes the binding process. It highlights how the variation in conformational and vibrational entropies associated with the constraints impacts the affinity.

Abstract

Macrocyclization constraints are widely used in the design of protein ligands to stabilize their bioactive conformation and increase their affinities. However, the resulting changes in binding entropy can be puzzling and uncorrelated to affinity gains. Here, the thermodynamic (Isothermal Titration Calorimetry) and structural (X-ray, NMR and CD) analysis of a complete series of lactam-bridged peptide ligands of the vascular endothelial growth factor, and their unconstrained analogs are reported. It is shown that differences in thermodynamics arise mainly from the folding energy of the peptide upon binding. The systematic reduction in conformational entropy penalty due to helix pre-organization can be counterbalanced by an unfavorable vibrational entropy change if the constraints are too rigid. The gain in configurational entropy partially escapes the enthalpy/entropy compensation and leads to an improvement in affinity. The precision of the analytical ITC method makes this study a possible benchmark for constrained peptides optimization.

A method was developed to convert lysine residues on peptides to Katritzky salts directly on solid support. These salts can then be used for a photochemical deaminative Csp³-Csp³ bond forming Giese reaction. The applicability of the reaction was demonstrated with various resins, all proteinogenic amino acids, and a variety of substrates.

Abstract

Introduction of unnatural amino acids can significantly improve the binding affinity and stability of peptides. Commercial availability of such amino acids is limited, and their synthesis is a long and tedious process. We here describe a method that allows the functionalization of peptides directly on solid-support by converting lysine residues to Katritzky salts, and subjecting them to a photochemical Giese reaction under mild reaction conditions. The method avoids the need for amino acid synthesis and instead offers a late-stage modification route for rapid peptide diversification. While numerous modification approaches at the lysine amine have been described, this work provides the first example of deaminative functionalization of peptides at lysine. The two-step protocol is compatible with various substrates, lysine analogues, resins, and all proteinogenic amino acids. Finally, by leveraging solid-phase modification, this protocol facilitates the functionalization of longer peptides as was demonstrated using biologically relevant peptides of up to 15 amino acids.

Synthesis
DOI: 10.1055/a-1868-4148

Vinyl sulfides accessed via Wittig olefination with thioalkylphosphonium salts are used as aldehyde- or ketone surrogates in Fischer indole reactions. These vinyl sulfides react with arylhydrazines in the presence of TsOH·H2O in refluxing ethanol or dichloroethane to yield diverse 3-substituted and 2,3-disubstituted indoles or azaindoles. The utility of this chemistry is highlighted with the efficient preparation of three biomedically relevant compounds: 4-aza-melatonin, a furoindoline, and an indomethacin-like CRTh2 antagonist.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
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Synthesis
DOI: 10.1055/a-1863-4082

A new approach for the synthesis of benzofurans starting from non-aromatic precursors is reported. The reaction involves sequential DBU-mediated cycloisomerization for furanylation followed by benzene ring construction via oxidative aromatization in the presence of Oxone®. Atom- and pot-economy, simple reaction conditions, the straightforward preparation of starting materials and access to diverse substituted benzofurans are the major advantages of this reaction.
[...]

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
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Synlett
DOI: 10.1055/a-1867-7228

A novel photoinduced strategy has been developed for the C–H amidation of aromatics and heteroaromatics by using benzamide radicals with free NH groups generated from N-amidopyridinium salts under visible-light irradiation. The new mode of activation of N-amidopyridinium salts proceeds efficiently under mild conditions to give various benzamide derivatives with free NH groups. In addition, oxazoline analogues, synthesized by the reaction with styrene, demonstrate a substantial range of prospective applications for this versatile protocol.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text