bims-cepepe 2025-01-05 papers

ACS Cent Sci. 2024 Dec 25. 10(12): 2242-2252

Combination of Coevolutionary Information and Supervised Learning Enables Generation of Cyclic Peptide Inhibitors with Enhanced Potency from a Small Data Set.

Ylenia Mazzocato, Nicola Frasson, Matthew Sample, Cristian Fregonese, Angela Pavan, Alberto Caregnato, Marta Simeoni, Alessandro Scarso, Laura Cendron, Petr Šulc, Alessandro Angelini.

Computational generation of cyclic peptide inhibitors using machine learning models requires large size training data sets often difficult to generate experimentally. Here we demonstrated that sequential combination of Random Forest Regression with the pseudolikelihood maximization Direct Coupling Analysis method and Monte Carlo simulation can effectively enhance the design pipeline of cyclic peptide inhibitors of a tumor-associated protease even for small experimental data sets. Further in vitro studies showed that such in silico-evolved cyclic peptides are more potent than the best peptide inhibitors previously developed to this target. Crystal structure of the cyclic peptides in complex with the protease resembled those of protein complexes, with large interaction surfaces, constrained peptide backbones, and multiple inter- and intramolecular interactions, leading to good binding affinity and selectivity.

DOI: https://doi.org/10.1021/acscentsci.4c01428

ACS Cent Sci. 2024 Dec 25. 10(12): 2294-2311

Cyclic Ruthenium-Peptide Prodrugs Penetrate the Blood-Brain Barrier and Attack Glioblastoma upon Light Activation in Orthotopic Zebrafish Tumor Models.

Liyan Zhang, Gangyin Zhao, Trevor Dalrymple, Yurii Husiev, Hildert Bronkhorst, Gabriel Forn-Cuní, Bruno Lopes-Bastos, Ewa Snaar-Jagalska, Sylvestre Bonnet.

The blood-brain barrier (BBB) presents one of the main obstacles to delivering anticancer drugs in glioblastoma. Herein, we investigated the potential of a series of cyclic ruthenium-peptide conjugates as photoactivated therapy candidates for the treatment of this aggressive tumor. The three compounds studied, Ru-p(HH), Ru-p(MH), and Ru-p(MM) ([Ru(Ph2phen)2 (Ac-X1RGDX2-NH2)]Cl2 with Ph2phen = 4,7-diphenyl-1,10-phenanthroline and X1, X2 = His or Met), include an integrin-targeted pentapeptide coordinated to a ruthenium warhead via two photoactivated ruthenium-X1,2 bonds. Their photochemistry, activation mechanism, tumor targeting, and antitumor activity were meticulously addressed. A combined in vitro and in vivo study revealed that the photoactivated cell-killing mechanism and their O2 dependence were strongly influenced by the nature of X1 and X2. Ru-p(MM) was shown to be a photoactivated chemotherapy (PACT) drug, while Ru-p(HH) behaved as a photodynamic therapy (PDT) drug. All conjugates, however, showed comparable antitumor targeting and efficacy toward human glioblastoma 3D spheroids and orthotopic glioblastoma tumor models in zebrafish embryos. Most importantly, in this model, all three compounds could effectively cross the BBB, resulting in excellent targeting of the tumors in the brain.

DOI: https://doi.org/10.1021/acscentsci.4c01173

J Pept Sci. 2025 Feb;31(2): e3667

Crystallographic Analysis of Short Helical Peptides Containing Homologs of Phenylalanine.

Mrinal Kalita, Archana, Ramesh Ramapanicker, Prema G Vasudev.

Interactions between aromatic side chains of amino acids stabilize the fold and assembly of short peptides. The aromatic π…π and C-H…π interactions have been widely explored in the design of short peptides with specific folding and aggregation patterns. In the present study, we investigated the effect of homologated phenylalanine side chains on the conformation and assembly of peptide helices through X-ray crystallographic structure determination and analysis of five pentapeptides. The parent peptide Boc-Phe-Aib-Aib-Leu-Phe-NHiPr (1) and its four variations were synthesized, in which either one or both of the Phe side chains have been modified by inserting one (homophenylalanine, hPhe; -CH2-CH2-C6H5) or two (h2Phe; -CH2-CH2-CH2-C6H5) additional CH2 groups in the side chain, and their crystal structures were analyzed. The results show that intramolecular aromatic interactions are not present in the parent peptide but are present in the peptides containing the higher homologs of Phe. In peptides that did not show intramolecular aromatic interactions, the effect of increased length of the side chain of Phe residues manifested as intermolecular interactions leading to ordered packing in crystals. The results indicate the potential of hPhe and h2Phe residues to have aromatic interactions that could induce preferential folding and aggregation of peptides containing them.

Keywords: aromatic interactions; crystal structure; homophenylalanine; peptides; side chain interactions

DOI: https://doi.org/10.1002/psc.3667

JACS Au. 2024 Dec 23. 4(12): 4866-4882

Structure-Based Design of "Head-to-Tail" Macrocyclic PROTACs.

Chungen Li, Yihan Chen, Weixue Huang, Yudi Qiu, Shengjie Huang, Yang Zhou, Fengtao Zhou, Jian Xu, Xiaomei Ren, Jinwei Zhang, Zhen Wang, Ming Ding, Ke Ding.

Macrocyclization is a compelling strategy for conventional drug design for improving biological activity, target specificity, and metabolic stability, but it was rarely applied to the design of PROTACs possibly due to the mechanism and structural complexity. Herein, we report the rational design of the first series of "Head-to-Tail" macrocyclic PROTACs. The resulting molecule SHD913 exhibited pronounced Brd4 protein degradation with low nM DC50 values while almost totally dismissing the "hook effect", which is a general character and common concern of a PROTAC, in multiple cancer cell lines. Further biological evaluation revealed that the compound exhibited positive cooperativity and induced de novo protein-protein interactions (PPIs) in both biophysical and cellular NanoBRET assays and outperformed macroPROTAC-1 that is the first reported macrocyclic Brd4 PROTAC, in cellular assays. In vitro liver microsomal stability evaluation suggested that SHD913 demonstrated improved metabolic stability in different species compared with the linear counterpart. The co-crystal structure of Brd4BD2: SHD913: VCB (VHL, Elongin C and Elongin B) complex determination and molecular dynamics (MD) simulation also elucidated details of the chemical-induced PPIs and highlighted the crucial contribution of restricted conformation of SHD913 to the ternary complex formation. These results collectively support that macrocyclization could be an attractive and feasible strategy for a new PROTAC design.

DOI: https://doi.org/10.1021/jacsau.4c00831