Novel octapeptide containing the RGD sequence as a potential anti-SARS-CoV-2 agent: design, synthesis, and theoretical studies

Tetrafluoroboric acid in trifluoroacetic acid, in the presence of thioanisole, has been found to cleave various protecting groups currently employed in Fmoc-based (Fmoc = fluoren-9-ylmethoxycarbonyl) solid-phase peptide synthesis without significant side reactions; this new deprotecting reagent has been successfully applied to the solid-phase synthesis of human glucagon (a 29 residue peptide) and α-MSH (a 13 residue peptide amide, acetyl-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2).

Extracellular matrix proteins in organ transplantation.

Dedicated to a peptide chemist of few words and immense impact: Louis A. Carpino

MIA (melanoma inhibitory activity) has been identified as a small protein secreted from malignant melanoma cells, which interacts with extracellular matrix proteins including fibronectin. Here, we show that MIA negatively regulates the activity of the mitogen-activated protein kinase pathway in malignant melanoma. Using far Western blotting and co-immunoprecipitation we searched for MIA-binding cell surface proteins. We found that MIA interacts with integrin alpha4beta1 and alpha5beta1, leading to down-regulation of integrin activity and reduction of mitogen-activated protein kinase signaling. These findings also suggest that MIA may play a role in tumor progression and the spread of malignant melanomas via mediating detachment of cells from extracellular matrix molecules by modulating integrin activity. Inhibiting MIA functions in vivo may therefore provide a novel therapeutic strategy for metastatic melanoma disease.

Stereospecific synthesis of 4-carboxyphenylalanine and derivatives for use in Fmoc-based solid-phase peptide synthesis

Aspartyl methyl ester formation via aspartimide ring opening: a proposed modification of the protocols used in Boc- and Fmoc-based solid-phase peptide synthesis

Phenylglycine racemization in Fmoc-based solid-phase peptide synthesis: Stereochemical stability is achieved by choice of reaction conditions

GVL is a green solvent used in Fmoc-based solid-phase peptide synthesis. It is susceptible to ring opening in the presence of bases such as piperidines, which are used to remove the Fmoc protecting group. Here we studied the formation of the corresponding acyl piperidides by time-dependent monitoring using NMR. The results, corroborated by theoretical calculations, indicate that a solution of piperidines in GVL should be prepared daily for a better Fmoc removal.

C-terminal peptide alpha-thioesters are valuable intermediates in the synthesis/semisynthesis of proteins by native chemical ligation. They are prepared either by solid-phase peptide synthesis (SPPS) or biosynthetically by protein splicing techniques. The present paper reviews the different methods available for the chemical synthesis of peptide alpha-thioesters using Fmoc-based SPPS.

Identification of Integrins Involved in Cell Adhesion to Native and Denatured Type I Collagens and the Phenotypic Transition of Rabbit Arterial Smooth Muscle Cells

We investigated the ultrasonication-mediated effects on the Fmoc-based solid-phase peptide synthesis (SPPS). Our study culminated with the development of an ultrasound-assisted strategy (US-SPPS) that allowed for the synthesis of different biologically active peptides (up to 44-mer), with a remarkable savings of material and reaction time. Noteworthy, ultrasonic irradiation did not exacerbate the main side reactions and improved the synthesis of peptides endowed with "difficult sequences", placing the US-SPPS among the current high-efficient peptide synthetic strategies.

Native chemical ligation is widely used for the convergent synthesis of proteins. The peptide thioesters required for this process can be challenging to produce, particularly when using Fmoc-based solid-phase peptide synthesis. We have previously reported a route to peptide thioesters, following Fmoc solid-phase peptide synthesis, via an N→S acyl shift that is initiated by the presence of a C-terminal cysteine residue, under mildly acidic conditions. Under typical reaction conditions, we occasionally observed significant thioester hydrolysis as a consequence of long reaction times (~48 h) and sought to accelerate the reaction. Here, we present a faster route to peptide thioesters, by replacing the C-terminal cysteine residue with selenocysteine and initiating thioester formation via an N→Se acyl shift. This modification allows thioester formation to take place at lower temperatures and on shorter time scales. We also demonstrate how application of this strategy also accelerates peptide cyclization, when a linear precursor is furnished with an N-terminal cysteine and C-terminal selenocysteine.

We report an efficient method to install electrophilic cysteine-selective ethynyl-phosphonamidates on peptides during Fmoc-based solid phase peptide synthesis (SPPS). By performing Staudinger-phosphonite reactions between different solid supported azido-peptides and varying ethynylphosphonites, we obtained ethynyl-phosphonamidate containing peptidic compounds after acidic deprotection, including an electrophilic cell-penetrating peptide that showed high efficiency as an additive for cellular delivery of proteins.

In this section, a novel approach for identifying MDM2-p53 and MDMX-p53 protein–protein interactions (PPIs) inhibitors by using chemically synthesized MDM2 and MDMX proteins has been established. MDM2 and MDMX are oncoproteins that negatively regulate the activity and stability of the tumor suppressor protein p53. The inhibitors of PPIs of MDM2-p53 and MDMX-p53 represent potential anticancer agents. Affinity-based chemical array screening is one of the efficient methods for identification of binding agents toward various pockets of proteins. To establish chemistry-based screening platform for identification of MDM2 and MDMX inhibitors, synthetic strategy of MDM2 and MDMX proteins and application of these proteins for chemical array screening were performed. MDM2 and MDMX proteins were prepared by Fmoc-based solid-phase peptide synthesis (SPPS), and binding candidates for them were identified from an in-house compound library by chemical array screening. The subsequent fluorescence polarization (FP) assay identified peptidic compounds that inhibited MDM2-p53 and MDMX-p53 interactions.

Malaria, caused by Plasmodium species and transmitted by Anopheles mosquitoes, continues to pose a significant global health threat. Pipecolisporin, a cyclic hexapeptide isolated from Nigrospora oryzae, has emerged as a promising antimalarial candidate due to its potent biological activity and stability. This study explores the synthesis, antimalarial activity, and computational studies of pipecolisporin, aiming to better understand its therapeutic potential. The peptide was successfully synthesized using Fmoc-based solid-phase peptide synthesis (SPPS) followed by cyclization in solution. The purified compound was characterized using HPLC and mass spectrometry, confirming a molecular ion peak at m/z [M + H]+ 692.4131, which matched the calculated mass. Structural verification through 1H- and 13C-NMR demonstrated strong alignment with the natural product. Pipecolisporin exhibited significant antimalarial activity with an IC50 of 26.0 ± 8.49 nM, highlighting its efficacy. In addition to the experimental synthesis, computational studies were conducted to analyze the interaction of pipecolisporin with key malaria-related enzymes, such as dihydrofolate reductase, plasmepsin V, and lactate dehydrogenase. These combined experimental and computational insights into pipecolisporin emphasize the importance of hydrophobic interactions, particularly in membrane penetration and receptor binding, for its antimalarial efficacy. Pipecolisporin represents a promising lead for future antimalarial drug development, with its efficacy, stability, and binding characteristics laying a solid foundation for ongoing research.