Peptidomimetic Derivatives Research Articles

Development of New Peptidomimetic NADPH Oxidase Inhibitors with Antithrombotic Properties.

The ability of synthetic peptides inhibitors of NOX1 to effectively block the production of ROS by the enzyme was studied with different methodologies. Specifically, taking advantage of our understanding of the active epitope of the regulatory NOX1 subunit NOXA1 as a potent inhibitor of NOX1-derived O2⋅- formation, a panel of peptidomimetic derivatives of this peptide were designed and synthesized with the aim of improving their activity and increasing their stability in plasma. The results highlighted that improved efficacy and potency was found for both the peptide-peptoid hybrid GS2, whereas stapled peptide AC5 and its precursor showed higher stability despite lower biological potency. This study showed that minimal structural modifications of NOXA1 peptides are required to improve both their potency and stability to finally achieve best candidates as new potential anti-thrombotic drugs.

Medicinal chemistry insights into antiviral peptidomimetics.

The (re)emergence of multidrug-resistant viruses and the emergence of new viruses highlight the urgent and ongoing need for new antiviral agents. The use of peptidomimetics as therapeutic drugs has often been associated with advantages, such as enhanced binding affinity, improved metabolic stability, and good bioavailability profiles. The development of novel antivirals is currently driven by strategies of converting peptides into peptidomimetic derivatives. In this review, we outline different structural modification design strategies for developing novel peptidomimetics as antivirals, involving N- or C-cap terminal structure modifications, pseudopeptides, amino acid modifications, inverse-peptides, cyclization, and molecular hybridization. We also present successful recent examples of peptidomimetic designs.

Novel peptide inhibitors targeting CD40 and CD40L interaction: A potential for atherosclerosis therapy

Atherosclerosis is a chronic inflammatory disease characterized by plaque build-up in the arteries, leading to the obstruction of blood flow. Macrophages are the primary immune cells found in the atherosclerotic lesions and are directly involved in atherosclerosis progression. Macrophages are derived from extravasating blood monocytes. The monocytic CD40 receptor is important for monocyte recruitment on the endothelium expressing the CD40 ligand (CD40L). Thus, targeting monocyte/macrophage interaction with the endothelium by inhibiting CD40-CD40L interaction may be a promising strategy for attenuating atherosclerosis. Monoclonal antibodies have been used against this target but shows various complications. We used an array of computer-aided drug discovery tools and molecular docking approaches to design a therapeutic inhibitory peptide that could efficiently bind to the critical residues (82Y, 84D, and 86N) on the CD40 receptor essential for the receptor's binding to CD40L. The initial screen identified a parent peptide with a high binding affinity to CD40, but the peptide exhibited a positive hepatotoxicity score. We then designed several novel peptidomimetic derivatives with higher binding affinities to CD40, good physicochemical properties, and negative hepatotoxicity as compared to the parent peptide. Furthermore, we conducted molecular dynamics simulations for both the apo and complexed forms of the receptor with ligand, and screened peptides to evaluate their stability. The designed peptidomimetic derivatives are promising therapeutics targeting the CD40-CD40L interaction and may potentially be used to attenuate atherosclerosis.

The impact of counterions in biological activity: case study of antibacterial alkylguanidino ureas.

Trifluoroacetic acid (TFA), due to its strong acidity and low boiling point, is extensively used in protecting groups-based synthetic strategies. Indeed, synthetic compounds bearing basic functions, such as amines or guanidines (commonly found in peptido or peptidomimetic derivatives), developed in the frame of drug discovery programmes, are often isolated as trifluoroacetate (TF-Acetate) salts and their biological activity is assessed as such in in vitro, ex vivo, or in vivo experiments. However, the presence of residual amounts of TFA was reported to potentially affect the accuracy and reproducibility of a broad range of cellular assays (e. g. antimicrobial susceptibility testing, and cytotoxicity assays) limiting the further development of these derivatives. Furthermore, the impact of the counterion on biological activity, including TF-Acetate, is still controversial. Herein, we present a focused case study aiming to evaluate the activity of an antibacterial AlkylGuanidino Urea (AGU) compound obtained as TF-Acetate (1a) and hydrochloride (1b) salt forms to highlight the role of counterions in affecting the biological activity. We also prepared and tested the corresponding free base (1c). The exchange of the counterions applied to polyguanidino compounds represents an unexplored and challenging field, which required significant efforts for the successful optimization of reliable methods of preparation, also reported in this work. In the end, the biological evaluation revealed a quite similar biological profile for the salt derivatives 1a and 1b and a lower potency was found for the free base 1c.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s11030-022-10505-6.

QSAR Modelling of Peptidomimetic Derivatives towards HKU4-CoV 3CLpro Inhibitors against MERS-CoV

In this paper, we report the relationship between the anti-MERS-CoV activities of the HKU4 derived peptides for some peptidomimetic compounds and various descriptors using the quantitative structure activity relationships (QSAR) methods. The used descriptors were computed using ChemSketch, Marvin Sketch and ChemOffice software. The principal components analysis (PCA) and the multiple linear regression (MLR) methods were used to propose a model with reliable predictive capacity. The original data set of 41 peptidomimetic derivatives was randomly divided into training and test sets of 34 and 7 compounds, respectively. The predictive ability of the best MLR model was assessed by determination coefficient R2 = 0.691, cross-validation parameter Q2cv = 0.528 and the external validation parameter R2test = 0.794.

Sustainable Synthesis of Novel Arylamide L-Cysteine Methyl Esters Peptidomimetic Derivatives: Inhibitors of Serine and Cysteine-like Proteases

The development of new protease inhibitors is always expanding for active therapies against diseases caused by pathogenic microorganisms that rely on proteases for replication and vital functions. This work aimed to synthesize new peptidomimetics arylamides, endeavoring to provide these compounds with the capacity to inhibit mainly cysteine and serine-like proteases. The effectiveness of COMU as coupling reagent, under classical and sustainable approaches, were evaluated. The results confirmed that the use of dichloromethane and the classical methodology is efficient for new amide bond formation in terms of yield. Although, the use of dimethyl carbonate and the microwave-assisted methodology proved competitive performance and can be used as an alternative route due to its environmentally friendly approach (green solvent and energy efficiency). In vitro screening assays attested that the proposed compounds have inhibitory activity for papain (IC50 between 5.56±0.21 μM and 18.50±0.69 μM) and β-trypsin (IC50 between 250±12 μM and 1410±30 μM). The compounds 1a and 1e were noteworthy with IC50 values of 5.56±0.21 μM and 7.06±0.33 μM for papain and 540±10 μM and 250±12 μM for β-trypsin, respectively. DOI: http://dx.doi.org/10.17807/orbital.v12i4.1575

Synthesis and Molecular Simulation Studies of Mandelic Acid Peptidomimetic Derivatives as Aminopeptidase N Inhibitors.

The aminopeptidase N (APN) over-expressed in tumor cells plays a critical role in angiogenesis which makes the development of APN inhibitors an attractive strategy for cancer research. It is clinically significant to develop potential APN inhibitors for cancer treatment. The design, synthesis, biological evaluation and molecular simulation of mandelic acid peptidomimetic derivatives as APN inhibitors are reported. Analysis of the binding mode of bestatin to APN led to the design and synthesis of mandelic acid peptidomimetic derivatives. APN inhibitory activities in vitro were evaluated by the spectrophotometric method. The binding mode of the target compounds with the APN binding site was studied relying on docking studies, molecular dynamics simulation experiments and binding energies calculation. The structures of target compounds were confirmed by IR, 1H-NMR and MS. All compounds exhibited a different range of inhibitory ability with IC50 values lying in the micromolar level. The compound 9m was found to be most potent as compared to other target derivatives. The molecular simulation revealed that ligand coordinating with the catalytic zinc ion is very important for inhibitory activities. The compound 9m might represent a promising scaffold for the further development of novel anti-cancer drugs.

Preparation and evaluation of 99m Tc-HYNIC-D (TPPE) as a new targeted imaging probe for detection of colon cancer: Preclinical comparison with 99m Tc-HYNIC-EPPT.

The aim of this study was to prepare radiolabeled peptide-based agents for imaging of colon cancer. According to the incorporation of HYNIC for radiolabeling with technetium-99m, two analogs were designed and compared: an antitumor-antibody-derived peptide based on the EPPT sequence and a novel retro-inverso peptidomimetic derivative D (TPPE) structurally modified by replacing the L-amino acids with D-amino acids and reversing the primary amino acid sequence of EPPT. The HYNIC-conjugated peptides were labeled with 99m Tc using tricine/EDDA coligand with more than 98% radiochemical yield and showed high metabolic stability. Kd values of 41.77±7.34nM and 37.33±8.37nM for 99m Tc-HYNIC-EPPT and 99m Tc-HYNIC-D (TPPE) confirmed high affinity of both peptides for cell surface antigen MUC1. These radiotracers demonstrated no significant differences in the cellular uptake and internalization value, but the biodistribution profile of 99m Tc-HYNIC-D (TPPE) was more favorable than that of 99m Tc-HYNIC-EPPT as a result of better tumor-to-non-target ratios for the examined tissues and organs. HT29 tumors were visualized more clearly in scintigraphic images with 99m Tc-HYNIC-D (TPPE) in comparison with 99m Tc-HYNIC-EPPT. The results showed the retro-inverso analog to be a more promising radiotracer as a probe for in vivo targeting of HT-29 tumors than the parent peptide.

99mTc-D(RGD): molecular imaging probe for diagnosis of αvβ3-positive tumors.

Arginine-glycine-aspartic acid (RGD) peptide with its specific binding affinity to integrin αvβ3, is widely investigated for the development of molecular imaging probes for diagnosis of αvβ3-positive tumors. The aim of this work was to evaluate the ability of Tc- HYNIC-D(RGD), a novel retro-inverso peptidomimetic derivative for U87MG tumor (αvβ3-positive) imaging. HYNIC-D(RGD) labeled with Tc using tricine/EDDA as an exchange coligands. Single-photon emission computed tomography imaging and biodistribution study were performed in nude mice bearing U87MG xenograft tumor. The labeling yield was >95%. The radiopeptide showed high uptake value in the U87MG tumor relative to muscle after 2 hours (1.43 ± 0.05 vs. 0.22 ± 0.11 %ID/g). The tumor/muscle ratio was 6.5. Blocking experiment showed specific binding towards tumor. Single-photon emission computed tomography imaging study revealed that radiopeptide had prominent uptake in U87MG tumor. The novel Tc HYNIC- D(RGD) was demonstrated to be a useful radiotracer for the assessment of αvβ3-positive tumor in animal model. Therefore, further clinical and preclinical studies are required.

99mTc labeled D(LPR): A novel retro-inverso peptide for VEGF receptor-1 targeted tumor imaging

IntroductionThe aim of this study was to evaluate the ability of D(LPR), a novel retro-inverso peptidomimetic derivative for imaging colon cancer. MethodsTwo different D(LPR) analogs were designed and compared based on conjugation of HYNIC at peptide's C or N terminal and then labeled with technetium-99m using tricine/EDDA as an exchange coligands. The radiolabeled conjugates were assessed for in vitro stability in saline and serum. The VEGFR-1 and NRP-1 receptors affinity, in vitro internalization and also dissociation Constance was evaluated. SPCET imaging and biodistribution studies were performed in nude mice bearing HT-29 xenograft tumors. ResultsBoth peptides labeled with technetium-99m in high radiochemical yield (˃97%). Peptide stability studies indicated a high metabolic stability of the radiopeptides in solution and serum. In vitro blocking studies demonstrated specific binding and internalization of [99mTc]Tc-HYNIC-peptides in cultured HUVEC cells. The Kd value for 99mTc-peptide 1 and 99mTc-peptide 2 were found to be 56.8 ± 12.9 nM and 71.6 ± 17.9 nM respectively. The tumor to muscle ratio was significant at 0.5 and 1 h after injection (4.5 and 4 for 99mTc-peptide 1 and 4.9 and 4.4 for 99mTc-peptide 2 at 0.5 and 1 h p.i. respectively). SPECT imaging studies revealed that both radioconjugates had prominent activity accumulation in VEGFR-1 and NRP-1 expressing HT-29 tumors. ConclusionThis study is the first instance of using a radiolabeled retro-inverso peptide for tumor imaging which is a promising tool to improve the performance of fragile peptide probes in vivo as imaging agents and warrant further investigations in other peptide-target systems.

Synthesis and molecular simulation study of furoic peptidomimetic derivatives as potent aminopeptodase N inhibitors.

The aminopeptidase N (APN) plays a critical role in angiogenesis and is over-expressed in tumor cells. In this paper, we report the synthesis and enzyme inhibition assay of furoic peptidomimetic compounds. These new compounds exhibit potent inhibitory ability toward APN with IC50 values lying in the micromolar level. The binding mode of inhibitors in APN active site was explained by a molecular simulation study. These data reveal that ligand coordinating with the catalytic Zn-ion is very important for inhibitory activities.

Cystatin C peptidomimetic derivative with antimicrobial properties as a potential compound against wound infections

A peptidomimetic called A20 (Cystapep 1) structurally based upon the N-terminal fragment of human cystatin C is known to have strong antibacterial properties. A20 is characterized by high activity against several bacterial strains often isolated from infected wounds, including methicillin-resistant S. aureus (MRSA). In this work we wanted to explore the therapeutic potential of A20 in the treatment of wound infections. We examined, cytotoxicity, allergenicity and impact of A20 on the proliferation and viability of human keratinocytes. Furthermore, the previously described antimicrobial action of A20has been confirmed here with reference strains of bacteria and extended by several other species. The A20 was highly active against Gram-positive bacteria with minimal inhibitory (MIC) and minimal bactericidal concentrations (MBC) between 8 and 128μg/mL. A20 did not affect proliferation of primary human keratinocytes in concentrations up to 50μg/mL. At the same time, it did not activate Peripheral Blood Mononuclear Cells (PBMCs), including basophils or neutrophils in vitro. Interestingly A20 was found to display immunomodulatory functions as it influences the production of Th2 cytokines (IL-4 and IL-13) by activated PBMCs. It was also resistant to degradation for at least 48h in human plasma. The results indicate that A20 is effective against the multiantibiotic-resistant bacteria and has a high safety profile, which makes it a promising antimicrobial drug candidate.

Design, synthesis, biological evaluation and molecular docking study on peptidomimetic analogues of XK469

XK469 is identified as a potent quinoxaline antineoplastic agent based on its significant clinical efficacy. It probably exerts its activity via DNA topoisomerase II (topo II) inhibition. To obtain more effective antineoplastic agents, a spectrum of peptidomimetic-type quinoxaline analogues of XK469 was herein designed, synthesized, and evaluated. Few compounds (e.g. 13a and 13b) exhibited obvious cytotoxicity indicated by in vitro anti-proliferative assay. SAR investigation revealed that introducing of hydrophobic tert-butylamine or dodecylamine moiety at the 3-position of quinoxaline core is favorable for achieving a better anti-proliferative potency, while peptidomimetic derivatives only yielded moderate cytotoxicity. Compounds with improved anti-proliferative activities also demonstrated decent anti-metastatic potencies comparable with that of doxorubicin (Doxo) based on in vivo mouse model study. The topo II-mediated kinetoplast DNA (kDNA) decatenation assay as well as molecular docking studies implicated that these compounds tend to be potent topo II inhibitors. Overall, compounds 13a and 13b, 13b in particular, standed out from various assessments and might be promising candidates for further chemical optimization.

A new procedure for N1-alkylation of imidazolidin-4-ones and its NMR characterization

N1-unsubstituted imidazolidin-4-ones of primaquine (PQ) can be stabilized by N1-alkylation under basic conditions. Here we report the development, with our conditions, of peptidomimetic derivatives of PQ with l-amino acid and alkyl derivatives. The new derivatives represent potential new therapeutics for use against protozoan parasites, through enzymatic protection of aminopeptidases.

The Melanocortin Receptor System: A Target for Multiple Degenerative Diseases.

The melanocortin receptor system consists of five closely related G-protein coupled receptors (MC1R, MC2R, MC3R, MC4R and MC5R). These receptors are involved in many of the key biological functions for multicellular animals, including human beings. The natural agonist ligands for these receptors are derived by processing of a primordial animal gene product, proopiomelanocortin (POMC). The ligand for the MC2R is ACTH (Adrenal Corticotropic Hormone), a larger processed peptide from POMC. The natural ligands for the other 4 melanocortin receptors are smaller peptides including α-melanocyte stimulating hormone (α-MSH) and related peptides from POMC (β-MSH and γ-MSH). They all contain the sequence His-Phe-Arg-Trp that is conserved throughout evolution. Thus, there has been considerable difficulty in developing highly selective ligands for the MC1R, MC3R, MC4R and MC5R. In this brief review, we discuss the various approaches that have been taken to design agonist and antagonist analogues and derivatives of the POMC peptides that are selective for the MC1R, MC3R, MC4R and MC5R receptors, via peptide, nonpeptide and peptidomimetic derivatives and analogues and their differential interactions with receptors that may help account for these selectivities.

Design, synthesis and anti-HIV-1 evaluation of hydrazide-based peptidomimetics as selective gelatinase inhibitors

As our ongoing work on research of gelatinase inhibitors, an array of hydrazide-containing peptidomimetic derivatives bearing quinoxalinone as well as spiro-heterocyclic backbones were designed, synthesized, and assayed for their in vitro enzymatic inhibitory effects. The results demonstrated that both the quinoxalinone (series I and II) and 1,4-dithia-7-azaspiro[4,4]nonane-based hydrazide peptidomimetics (series III) displayed remarkably selectivity towards gelatinase A as compared to APN, with IC50 values in the micromole range. Structure–activity relationships were herein briefly discussed. Given evidences have validated that gelatinase inhibition may be contributable to the therapy of HIV-1 infection, all the target compounds were also submitted to the preliminary in vitro anti-HIV-1 evaluation. It resulted that gelatinase inhibition really has positive correlation with anti-HIV-1 activity, especially compounds 4m and 7h, which gave enhanced gelatinase inhibition in comparison with the positive control LY52, and also decent anti-HIV-1 potencies. The FlexX docking results provided a straightforward insight into the binding pattern between inhibitors and gelatinase, as well as the selective inhibition towards gelatinase over APN. Collectively, our research encouraged potent gelatinase inhibitors might be used in the development of anti-HIV-1 agents. And else, compounds 4m and 7h might be promising candidates to be considered for further chemical optimization.

Synthesis and Antiproliferative Activity of Thiadiazole Peptidomimetic Derivatives

Synthesis and Antiproliferative Activity of Thiadiazole Peptidomimetic Derivatives

Docking and QM/MM Studies of NS2B-NS3pro Inhibitors: a Molecular Target against the Dengue Virus

Dengue virus (DENV) has been characterized as having great clinical importance in the world, as there is no specific treatment against this virus. The NS2B-NS3pro complex is essential for the replication and maturation of DENV and is a potential pharmacological target. The present study aims to evaluate and understand the interactions and affinities (via molecular docking/AutoDock Vina) of 16 peptidomimetic derivatives applied to a NS2B-NS3pro DENV-2 complex constructed by homology modeling (via SWISS-MODEL). Two compounds were selected as potential inhibitors of this protein complex. In addition, these compounds possess important interactions involving Ser135, Gly169 and Tyr161, which have been described previously to be fundamental to the recognition of inhibitors directed to this receptor. Thus, the involvement of these residues is significant pharmacologically because they may contribute to the inhibitory action of this molecular target against DENV.

Chitosan based nanoparticles functionalized with peptidomimetic derivatives for oral drug delivery

The goal of this study was to develop an optimized drug delivery carrier for oral mucosa applications able to release in situ bioactive molecules by using biopolymeric materials. Among them chitosan and poly(lactic-co-glycolic acid) (PLGA) have gained considerable attention as biocompatible carriers able to improve the delivery of active agents. The formulation of such vehicles in the form of nanoparticles (NPs) could permit to exploit the peculiar properties of nanomaterials in order to enhance the efficacy of active agents. Chitosan (CS) and PLGA chlorexidine dihydrochloride (CHX)-loaded NPs were synthesized by ionotropic gelation and osmosis based methodology respectively. In order to facilitate NPs adhesion on human dental surfaces, two different strategies were employed: PLGA particles with an external shell of CS to produce a positive surface charge allowing CHX loaded PLGA NPs to interact with the negative charged dental surfaces, while CS particles were functionalized with peptidomimetic derivative glutathione (GSH). The morphology was investigated by scanning electron microscopy. A sustained release profile of CHX from CS NPs was achieved. CS-based NPs adhered on human tooth surfaces in a simulated brushing and rinsing process and their in vitro toxicity evaluation on Human Gingival Fibroblasts (HGFs) was between 20 and 60% in all experimental conditions. Thanks to their adhesion properties and low cytotoxicity, the synthesized CS-based formulations may be efficiently exploited for therapy purposes or to enhance in vivo dental care (i.e. preparation of toothpastes or other cosmetics for daily oral care).

Development of novel neurokinin 3 receptor (NK3R) selective agonists with resistance to proteolytic degradation.

Neurokinin B (NKB) regulates the release of gonadotropin-releasing hormone (GnRH) via activation of the neurokinin-3 receptor (NK3R). We evaluated the biological stability of NK3R selective agonists to develop novel NK3R agonists to regulate reproductive functions. On the basis of degradation profiles, several peptidomimetic derivatives were designed. The modification of senktide with (E)-alkene dipeptide isostere generated a novel potent NK3R agonist with high stability and prolonged bioactivity.