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Myb was identified over four decades ago as the transforming component of acute leukemia viruses in chickens. Since then it has become increasingly apparent that dysregulated MYB activity characterizes many blood cancers, including acute myeloid leukemia, and that it represents the most "addictive" oncoprotein in many, if not all, such diseases. As a consequence of this tumor-specific dependency for MYB, it has become a major focus of efforts to develop specific antileukemia drugs. Much attention is being given to ways to interrupt the interaction between MYB and cooperating factors, in particular EP300/KAT3B and CBP/KAT3A. Aside from candidates identified through screening of small molecules, the most exciting prospect for novel drugs seems to be the design of peptide mimetics that interfere directly at the interface between MYB and its cofactors. Such peptides combine a high degree of target specificity with good efficacy including minimal effects on normal hematopoietic cells.

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BACKGROUND: Cationic antimicrobial peptides (AMPs) possess broad-spectrum biological activities with less inclination to inducing antibiotic resistance. Herein a battery of amphiphilic amidines were designed by mimicking the characteristics of AMPs. The antifungal activities and the effects to the hyphal morphology and membrane permeability were investigated. RESULTS: The results indicated the inhibitory rates of ten compounds were over 80% to Botrytis cinerea and ten compounds over 90% to Valsa mali Miyabe et Yamada at 50 mg L-1. The half maximal effective concentration (EC50) values of compound 5g and 6g to V. mali were 1.21 and 1.90 mg L-1 respectively. The protective rate against apple canker of compound 5g reached 93.4% at 100 mg L-1 on twigs, superior to carbendazim (53.3%). When treated with 5g, the cell membrane permeability and leakage of content of V. mali increased, accompanied with the decrease of superoxide dismutase (SOD) and catalase (CAT) level. Concurrently, the mycelial hyphae contracted, wrinkled, and collapsed, providing evidence of membrane perturbation. A three-dimensional quantitative structure-activity relationship (3D-QSAR) between the topic compounds and the EC50 to V. mali was established showing good predictability (r2 = 0.971). CONCLUSION: Amphiphilic amidines can acquire antifungal activities by acting on the plasmic membrane. Compound 5g could be a promising lead in discovering novel fungicidal candidates. © 2024 Society of Chemical Industry.

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Traumatic brain injury (TBI) is a leading cause of disability in adults, caused by a physical insult damaging the brain. Growth factor-based therapies have the potential to reduce the effects of secondary injury and improve outcomes by providing neuroprotection against glutamate excitotoxicity, oxidative damage, hypoxia, and ischemia, as well as promoting neurite outgrowth and the formation of new blood vessels. Despite promising evidence in preclinical studies, few neurotrophic factors have been tested in clinical trials for TBI. Translation to the clinic is not trivial and is limited by the short in vivo half-life of the protein, the inability to cross the blood-brain barrier and human delivery systems. Synthetic peptide mimetics have the potential to be used in place of recombinant growth factors, activating the same downstream signalling pathways, with a decrease in size and more favourable pharmacokinetic properties. In this review, we will discuss growth factors with the potential to modulate damage caused by secondary injury mechanisms following a traumatic brain injury that have been trialled in other indications including spinal cord injury, stroke and neurodegenerative diseases. Peptide mimetics of nerve growth factor (NGF), hepatocyte growth factor (HGF), glial cell line-derived growth factor (GDNF), brain-derived neurotrophic factor (BDNF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) will be highlighted, most of which have not yet been tested in preclinical or clinical models of TBI.

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The need for rapidly developed diagnostic tests has gained significant attention after the recent pandemic. Production of neutralizing antibodies for vaccine development or antibodies to be used in diagnostic tests usually require the usage of recombinant proteins representing the infectious agent. However, peptides that can mimic these recombinant proteins may be rapidly utilized, especially in emergencies such as the recent outbreak. Here, we report two peptides that mimic the receptor binding domain of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and investigate their binding behavior against the corresponding human immunoglobulin G and immunoglobulin M (IgG and IgM) antibodies in a clinical sample using a quartz crystal microbalance (QCM) sensor. These peptides were immobilized on a QCM sensor surface, and their binding behavior was studied against a clinical serum sample that was previously determined to be IgG and IgM-positive. It was determined that designed peptides bind to SARS-CoV-2 antibodies in a clinical sample. These peptides might be useful for the detection of SARS-CoV-2 antibodies using different methods such as enzyme-linked immunosorbent assay (ELISA) or lateral flow assays. A similar platform might prove to be useful for the detection and development of antibodies in other infections.

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A number of viruses that have caused wide spread concern e.g. Ebola, Zika, and SARS-CoV2 (severe acute respiratory syndrome coronavirus 2 also known as COVID 19) have at various times, become newsworthy as a result of being newly discovered, mutations enabling them to more efficiently infect humans or modern modes of transportation moving them to areas with naive, susceptible populations. As more is learned about the mechanisms whereby these pathogens enter human cells it has become increasingly evident that carbohydrates expressed on the surface of either target cells or the pathogens themselves are essential. Variability in carbohydrate structures as well as the presence of carbohydrate binding receptors (lectins) provides a plethora of potential binding interactions by which infection of cells can occur. Identification of specific lipid- or protein-associated carbohydrates essential for infection provides support for research being done to develop carbohydrate related inhibitors of those interactions. This chapter (1) discusses scenarios for how carbohydrates affect the ability of specific infectious agents to interact with neural cells, (2) gives examples of problems that may result from development of antibodies to carbohydrate antigens found on pathogens that are similar to epitopes expressed on mammalian cells, and (3) provides examples of approaches either in use or under consideration for translational uses of this information.

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Brain-derived neurotrophic factor (BDNF) is a neurotrophin (NT) essential for neuronal development and synaptic plasticity. Dysregulation of BDNF signaling is implicated in different neurological disorders. The direct NT administration as therapeutics has revealed to be challenging. This has prompted the design of peptides mimicking different regions of the BDNF structure. Although loops 2 and 4 have been thoroughly investigated, less is known regarding the BDNF N-terminal region, which is involved in the selective recognition of the TrkB receptor. Herein, a dimeric form of the linear peptide encompassing the 1-12 residues of the BDNF N-terminal (d-bdnf) was synthesized. It demonstrated to act as an agonist promoting specific phosphorylation of TrkB and downstream ERK and AKT effectors. The ability to promote TrkB dimerization was investigated by advanced fluorescence microscopy and molecular dynamics (MD) simulations, finding activation modes shared with BDNF. Furthermore, d-bdnf was able to sustain neurite outgrowth and increase the expression of differentiation (NEFM, LAMC1) and polarization markers (MAP2, MAPT) demonstrating its neurotrophic activity. As TrkB activity is affected by zinc ions in the synaptic cleft, we first verified the ability of d-bdnf to coordinate zinc and then the effect of such complexation on its activity. The d-bdnf neurotrophic activity was reduced by zinc complexation, demonstrating the role of the latter in tuning the activity of the new peptido-mimetic. Taken together our data uncover the neurotrophic properties of a novel BDNF mimetic peptide and pave the way for future studies to understand the pharmacological basis of d-bdnf action and develop novel BDNF-based therapeutic strategies.

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Baby Boom (BBM) is a key transcription factor that triggers embryogenesis, enhances transformation and regeneration efficiencies, and regulates developmental pathways in plants. Triggering or activating BBM in non-model crops could overcome the bottlenecks in plant breeding. Understanding BBM's structure is critical for functional characterization and determination of interacting partners and/or ligands. The current in silico study aimed to study BBM's sequence and conservation across all plant proteomes, predict protein-protein and protein-ligand interactions, and perform molecular docking and molecular dynamics (MD) simulation to specifically determine the binding site amino acid residues. In addition, peptide sequences that interact with BBM have also been predicted, which provide avenues for altered functional interactions and the design of peptide mimetics that can be experimentally validated for their role in tissue culture or transformation media. This novel data could pave the way for the exploitation of BBM's potential as the master regulator of specialized plant processes such as apomixes, haploid embryogenesis, and CRISPR/Cas9 transgenic development.

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Peptide5 is a 12-amino acid mimetic peptide that corresponds to a region of the extracellular loop 2 (EL2) of connexin43. Peptide5 regulates both cellular communication with the cytoplasm (hemichannels) and cell-to-cell communication (gap junctions), and both processes are implicated in neurological pathologies. To address the poor in vivo stability of native peptide5 and to improve its activity, twenty-five novel peptide5 mimetics were designed and synthesized. All the analogues underwent biological evaluation as a hemichannel blocker and as a gap junction disruptor, and several were assessed for stability in human serum. From this study, it was established that several acylations on the N-terminus were tolerated in the hemichannel assay. However, the replacement of the L-Lys with an N-methylated L-Lys to give H-VDCFLSRPTE-N-MeKT-OH showed good hemichannel and gap junction activity and was more stable in human serum. The cyclic peptide variants generally were not tolerated in either the hemichannel and gap junction assay although several possessed outstanding stability in human serum.

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Teraryl-based α-helix mimetics have proven to be useful compounds for the inhibition of protein-protein interactions (PPI). We have developed a modular and flexible approach for the synthesis of teraryl-based α-helix mimetics using a benzene core unit featuring two leaving groups of differentiated reactivity in the Pd-catalyzed cross-coupling used for teraryl assembly. In previous publications we have introduced the methodology of 4-iodophenyltriflates decorated with the side chains of some of the proteinogenic amino acids. We herein report the core fragments corresponding to the previously missing amino acids Arg, Asn, Asp, Met, Trp and Tyr. Therefore, our set now encompasses all relevant amino acid analogues with the exception of His. In order to be compatible with the triflate moiety, some of the nucleophilic side chains had to be provided in a protected form to serve as stable building blocks. Additionally, cross-coupling procedures for the assembly of teraryls were investigated.

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Teraryl-based α-helix mimetics have proven to be useful compounds for the inhibition of protein-protein interactions (PPI). We have developed a modular and flexible approach for the synthesis of teraryl-based α-helix mimetics using a benzene core unit featuring two halide leaving groups of differentiated reactivity in the Pd-catalyzed cross-coupling used for teraryl assembly. The use of para-bromo iodoarene core fragments resolved the issue of hydrolysis during cross-coupling that was observed when using triflate as a leaving group. We report a complete set of para-bromoiodoarene core fragments decorated with side chains of all proteinogenic amino acids relevant for PPI (Ala, Arg, Asn, Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met, Phe, Ser, Thr, Trp, Tyr and Val). In order to be compatible with general cross-coupling conditions, some of the nucleophilic side chains had to be provided in a protected form to serve as stable building blocks.

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Teraryl-based α-helix mimetics have proven to be useful compounds for the inhibition of protein-protein interactions (PPI). We have developed a modular and flexible approach for the synthesis of teraryl-based α-helix mimetics using pyridine containing boronic acid building blocks to increase the water solubility. Following our initial publication in which we have introduced the methodology in combination with sequential Pd-catalyzed cross-coupling for teraryl assembly, we can now report a complete set of pyridine based boronic acid building blocks decorated with side chains of all proteinogenic amino acids relevant for PPI (Ala, Arg, Asn, Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met, Phe, Ser, Thr, Trp, Tyr, Val) to complement the core fragment set. For a representative set of teraryls we have studied the influence of the pyridine rings on the solubility of the assembled oligoarenes.

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An aromatic substituent has been introduced into a known hydroxyethylamine (HEA)-type BACE1 inhibitor containing the superior substrate sequence to enhance inhibitory activity. The HEA-type isosteres bearing different hydroxyl group and methyl group configurations were prepared through a branched synthesis approach using intra- and inter-molecular epoxide opening reactions. The effect of their configuration was evaluated, showing that an R-configuration improved the inhibitory activity, while introduction of a methyl group on the isostere decreased the activity. Based on the non-substituted isostere with an R-configuration, 21 derivatives containing various substituents at the P1' site were synthesized. Our evaluation of the derivatives showed that the structure of the P1' site had a clear effect on activity, and highly potent inhibitor 40g, which showed sub-micromolar activity against recombinant BACE1 (rBACE1), was identified. The docking simulation of 40g with rBACE1 suggested that a carboxymethyl group at the para-position of the P1' benzene ring interacted with Lys285 in the S1' pocket.

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Battling metastasis through inhibition of cell motility is considered a promising approach to support cancer therapies. In this context, Ena/VASP-depending signaling pathways, in particular interactions with their EVH1 domains, are promising targets for pharmaceutical intervention. However, protein-protein interactions involving proline-rich segments are notoriously difficult to address by small molecules. Hence, structure-based design efforts in combination with the chemical synthesis of additional molecular entities are required. Building on a previously developed nonpeptidic micromolar inhibitor, we determined 22 crystal structures of ENAH EVH1 in complex with inhibitors and rationally extended our library of conformationally defined proline-derived modules (ProMs) to succeed in developing a nanomolar inhibitor ([Formula: see text] Da). In contrast to the previous inhibitor, the optimized compounds reduced extravasation of invasive breast cancer cells in a zebrafish model. This study represents an example of successful, structure-guided development of low molecular weight inhibitors specifically and selectively addressing a proline-rich sequence-recognizing domain that is characterized by a shallow epitope lacking defined binding pockets. The evolved high-affinity inhibitor may now serve as a tool in validating the basic therapeutic concept, i.e., the suppression of cancer metastasis by inhibiting a crucial protein-protein interaction involved in actin filament processing and cell migration.

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INTRODUCTION: Connexin and pannexin (hemi)channels play an important role in paracrine and autocrine signaling pathways. The opening of these cellular pores is linked to a wide range of diseases. Therefore, pharmacological closing of connexin and pannexin (hemi)channels seems a promising therapeutic strategy. However, the currently available inhibitors cope with recurring problems concerning selectivity, specificity, stability and/or solubility. AREAS COVERED: A number of peptides that mimic specific regions in the native sequence of connexins and pannexins have the potential to overcome some of these hurdles. In this paper, an overview is provided on these peptide-based inhibitors of connexin and pannexin (hemi)channels for therapeutic purposes. The authors also provide the reader with their expert perspectives on the future of these peptide-based inhibitors. EXPERT OPINION: Peptide mimetics can become valuable tools in the treatment of connexin-related and pannexin-related diseases. This can be made possible provided that available peptides are optimized, and new peptide mimetics are designed based on knowledge of the mechanisms underlying the gating control of connexin and pannexin (hemi)channels.

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A general and powerful method for the stereo-controlled Pd-catalyzed N-allylation of amino acid esters is reported, as a previously largely unsolved synthetic challenge. Employing a new class of tartaric acid-derived C2 -symmetric chiral diphosphane ligands the developed asymmetric amination protocol allows the conversion of various amino acid esters to the N-allylated products with highest levels of enantio- or diastereoselectivity in a fully catalyst-controlled fashion and predictable configuration. Remarkably, the in situ generated catalysts also exhibit outstanding levels of activity (ligand acceleration). The usefulness of the method was demonstrated in the stereo-divergent synthesis of a set of new conformationally defined dipeptide mimetics, which represent new modular building blocks for the development of peptide-inspired bioactive compounds.

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Lipoproteins are endogenous nanoparticles which are the major transporter of fats and cholesterol in the human body. They play a key role in the regulatory mechanisms of cardiovascular events. Lipoproteins can be modified and manipulated to act as drug delivery systems or nanocarriers for contrast agents. In particular, high density lipoproteins (HDL), which are the smallest class of lipoproteins, can be synthetically engineered either as nascent HDL nanodiscs or spherical HDL nanoparticles. Reconstituted HDL (rHDL) particles are formed by self-assembly of various lipids and apolipoprotein AI (apo-AI). A variety of substances including drugs, nucleic acids, signal emitting molecules, or dyes can be loaded, making them efficient nanocarriers for therapeutic applications or medical diagnostics. This review provides an overview about synthesis techniques, physicochemical properties of rHDL nanoparticles, and structural determinants for rHDL function. We discuss recent developments utilizing either apo-AI or apo-AI mimetic peptides for the design of pharmaceutical rHDL formulations. Advantages, limitations, challenges, and prospects for clinical translation are evaluated with a special focus on promising strategies for the treatment and diagnosis of atherosclerosis and cardiovascular diseases.

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Introduction: Nosocomial pneumonia is the second most common infection in hospital settings, resulting in substantial increases in morbidity, mortality, and length of hospital stay. The rapid increase in resistance of nosocomial pathogens to many antibiotics and the high dissemination of resistance genes highlight the need for innovative approaches to combat difficult-to-treat nosocomial respiratory infections. Areas covered: This review summarizes the synthetic antimicrobials that are currently in development for the treatment of nosocomial pneumonia, focusing on antibiotics in the final phases of clinical development and on the strategies employed by novel synthetic antimicrobial peptides. Expert opinion: Several novel synthetic antimicrobials are currently in the pipeline, and it appears that new antimicrobial peptides or mimetics will soon be made available, expanding the opportunities to treat nosocomial pneumonia. However, the approval process for use in the treatment of nosocomial pneumonia is arduous. Given that significant investments by pharmaceutical companies have ended in failure to obtain the approval of regulatory agencies, novel platforms for antimicrobial discovery are needed. The identification of new and fully synthetic chemical structures with activity against nosocomial pathogens needs to be followed by preclinical studies in large animals and by pharmacokinetic and pharmacodynamic studies in specific critically ill populations to assess lung penetration.

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Host-defense peptides (HDPs) have an important therapeutic potential against microbial infections but their metabolic instability and cellular cytotoxicity have limited their utility. To overcome these limitations, we utilized five small-molecule, nonpeptide HDP mimetics (smHDPMs) and tested their effects on cytotoxicity, antimicrobial activity, and mast cell (MC) degranulation. None of the smHDPMs displayed cytotoxicity against mouse 3T3 fibroblasts or human transformed liver HepG2 cells. However, one compound had both antifungal and antibacterial activity. Surprisingly, all five compounds induced degranulation in a human MC line, LAD2, and this response was substantially reduced in Mas-related G protein-coupled receptor (GPCR)-X2 (MRGPRX2)-silenced cells. Furthermore, all five compounds induced degranulation in RBL-2H3 cells expressing MRGPRX2 but this response was abolished in cells expressing naturally occurring loss-of-function missense variants G165E (rs141744602) and D184H (rs372988289). Mrgprb2 is the likely mouse ortholog of human MRGPRX2, which is expressed in connective tissue MCs (CTMCs) such as cutaneous and peritoneal MCs (PMCs). All five smHDPMs induced degranulation in wild-type PMCs but not in cells derived from Mrgprb2⁻/⁻ mice. These findings suggest that smHDPMs could serve as novel targets for the treatment of drug-resistant fungal and bacterial infections because of their ability to harness CTMCs' host defense functions.

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Apelins are human peptide hormones with various physiological activities, including the moderation of cardiovascular, renal, metabolic and neurological function. Their potency is dependent on and limited by proteolytic degradation in the circulatory system. Here we identify human plasma kallikrein (KLKB1) as a protease that cleaves the first three N-terminal amino acids (KFR) of apelin-17. The cleavage kinetics are similar to neprilysin (NEP), which cleaves within the critical 'RPRL'-motif thereby inactivating apelin. The resulting C-terminal 14-mer after KLKB1 cleavage has much lower biological activity, and the presence of its N-terminal basic arginine seems to negate the blood pressure lowering effect. Based on C-terminally engineered apelin analogs (A2), resistant to angiotensin converting enzyme 2 (ACE2), attachment of an N-terminal C16 fatty acid chain (PALMitoylation) or polyethylene glycol chain (PEGylation) minimizes KLKB1 cleavage of the 17-mers, thereby extending plasma half-life while fully retaining biological activity. The N-terminally PEGylated apelin-17(A2) is a highly protease resistant analog, with excellent apelin receptor activation and pronounced blood pressure lowering effect.

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A series of our previously described BH3 peptide mimetics derived from Bim-BH3 domain core region were found to exhibit weak to potent PTP1B binding affinity and inhibitory activities via target-based drug screening. Among these compounds, a 12-aa Bim-BH3 core sequence peptide conjugated to palmitic acid (SM-6) displayed good PTP1B binding affinity (KD = 8.38 nmol/L), inhibitory activity (IC50 = 1.20 µmol/L) and selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). Furthermore, SM-6 promoted HepG2 cell glucose uptake and inhibited the expression of PTP1B, indicating that SM-6 could improve the insulin resistance effect in the insulin-resistant HepG2 cell model. These results may indicate a new direction for the application of BH3 peptide mimetics and promising PTP1B peptide inhibitors could be designed and developed based on SM-6.

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