The design of bioactive marine peptides as a HIV-1 protease inhibitor

Background: Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV or AIDS) is a disease related to the human immune system. Given its important role in viral replication, HIV1 protease (HIV1 PR) becomes the major therapeutic target in the treatment of AIDS. In this case, we need a dynamic aspect of molecular interactions that can demonstrate the important role of conformational variability in the design of HIV1 PR inhibitors. There are several inhibitor candidates from marine organisms, such as the LLEYSL and LLEYSI bioactive peptides produced by oysters (Crassostrea gigas). Objective: Proteinpeptide docking method was used in silico to identify, evaluate, and explore the molecular interactions between bioactive peptide molecules and HIV-1 protease macromolecules. Methods: The sequencing of bioactive peptide molecules was modeled into 3D conformation using the PEPFOLD software. The best conformation was chosen for the study of molecular interactions against HIV1 protease macromolecules using the PatchDock software. The molecular interactions formed were further observed using the BIOVIA Discovery Studio 2020 software. Results: The results of this study indicated that the LLEYSL bioactive peptide had the best affinity with an ACE score of minus 1284.70 kJ per mol. Conclusion: Bioactive peptide molecule is predicted to be a candidate for HIV1 protease inhibitor. Keywords: AIDS, HIV1 protease, bioactive peptides, protein-peptide docking, in silico

Supramolecular peptide nano-assemblies for cancer diagnosis and therapy: from molecular design to material synthesis and function-specific applications

Peptide molecule has high bioactivity, good biocompatibility, and excellent biodegradability. In addition, it has adjustable amino acid structure and sequence, which can be flexible designed and tailored to form supramolecular nano-assemblies with specific biomimicking, recognition, and targeting properties via molecular self-assembly. These unique properties of peptide nano-assemblies made it possible for utilizing them for biomedical and tissue engineering applications. In this review, we summarize recent progress on the motif design, self-assembly synthesis, and functional tailoring of peptide nano-assemblies for both cancer diagnosis and therapy. For this aim, firstly we demonstrate the methodologies on the synthesis of various functional pure and hybrid peptide nano-assemblies, by which the structural and functional tailoring of peptide nano-assemblies are introduced and discussed in detail. Secondly, we present the applications of peptide nano-assemblies for cancer diagnosis applications, including optical and magnetic imaging as well as biosensing of cancer cells. Thirdly, the design of peptide nano-assemblies for enzyme-mediated killing, chemo-therapy, photothermal therapy, and multi-therapy of cancer cells are introduced. Finally, the challenges and perspectives in this promising topic are discussed. This work will be useful for readers to understand the methodologies on peptide design and functional tailoring for highly effective, specific, and targeted diagnosis and therapy of cancers, and at the same time it will promote the development of cancer diagnosis and therapy by linking those knowledges in biological science, nanotechnology, biomedicine, tissue engineering, and analytical science.

A Novel Vaccine RNA-peptide against HIV-1: Exosomes as Carrier in Viral Progression

Introduction of a new drug/vaccine model against HIV-1 with prophylactic and therapeutic actions, also useful, in HIV-1 rehabilitation. This RNA-peptide vaccine projects involving RNA from SARS-CoV-2, and peptides from human HIV-1 and human PARP-1 proteins. As mRNA target, we used primers miRNA repertoire and host immune factor regulation upon avian coronavirus infection in eggs. The primers were modified with poly adenine (A) target. We designed the peptides target from HIV-1 protein and PARP-1 human protein. Our analysis, according to the algorithms Cruz Rodriguez (CR) identified an RNA-peptide with theorical fusion value stability FS=80.04 cruz, EA= 97.22 ro and BA= 1.21 to treat HIV-1. Where, we are proposing, the exosomes and how these vesicles could function as carriers of our RNA-peptide molecule. In this study, we expect that major histocompatibility complex l (MHC l) bind the molecule peptide (B) generated by hydrolysis (DEVD) of molecule RNA-peptide (AB) after induction of apoptosis pathways by caspase 3 or caspase 7. Also, we expect that major histocompatibility complex ll (MHC ll) bind the molecule RNA-peptide (A) generated and recognition by appropriate T-cells at the infected cell with HIV-1.

The Algorithms Cruz Rodriguez (CR) are Proposing A Novel Vaccine RNA-Peptide against Breast, Ovarian, and Lung Cancers Disease: Exosomes as Carrier in Cancer Progression and Metastasis

Exosomes are a novel horizon in modern therapy and open exciting new opportunities for advanced drug transport and targeted release. Exosomes are biological nanoparticles with dimensions ranging from 30 to 100 nm and are generated by all cell types in the human body. Exosomes-which are extracellular vesicles that function in intercellular communication-may play a key role in the dissemination of vaccine as well as host-derived molecules during cancer disease. We highlight the composition and function of exosomes produced during cancer disease in our work, how these vesicles could function as carriers of the RNA-peptide molecule. Finally, according to the algorithms CRUZ RODRIGUEZ (CR) we are proposing various methods to develop a novel vaccine against breast, ovarian, and lung cancers. Therefore, six RNA-peptides from our previous study were chosen based on the potential of inducing strong fusion stability (FS=58.50 cruz) and exosome affinity (EA=59.80 ro), Biological Action (BA= 1.0223 ro/cruz). This result may lead to the development of promising new therapeutic approaches in cancer management by using exosome-mediated miRNA-peptide vaccine therapy. Due to, according to the algorithm CR the Optimal Biological Action (OBA) value for antitumoral RNA-peptide with Exosome as carrier are: 0.8 < OBA < 1.3. These results suggest that the designed vaccine can elicit specific immune responses against three types of cancer; however, these results need experimental studies to confirm the efficacy and safety profile of the proposed vaccine structure.

Medicago Sativa Defensin 1 (MsDef1), A Natural Tumor Targeted Sensitizer for Improving Chemotherapy: Translation from Anti-Fungal Agent to Potential Anti-Cancer Agent

IntroductionMsDef1, a 45-amino acid cysteine-rich peptide from the seed of Medicago sativa is an antifungal defensin small protein. It exhibits broad-spectrum antifungal activity against fungal pathogens of plants at low micromolar concentrations. The common vulnerability of fungal and cancer cells determines the utility of MsDef1 as a potential anti-tumor agent.ResultsThe solution dynamics of 15N-labeled MsDef1, 15N longitudinal relaxation (T1) and 15N-1H Nuclear Overhauser Effect (NOE) shows that GlcCer binds at two sites on the peptide molecule, i.e., Asp36-Cys39 and amino acids between 12-20 and 33-40. MsDef1 interacts with drug resistant breast cancer MCF-7R cells, permeates GlcCer-rich plasma membrane and releases apoptotic ceramide. This results in the activation of ceramide pathway involving interaction of the peptide with intracellular thioredoxin (Trx), another tumor specific biomarker. MsDef1 oxidizes Trx through four S-S bonds and in the process, gets reduced to thiols. Oxidation of Trx is correlated with the activation of Apoptosis Stimulating Kinase 1 (ASK1) which is known to sensitize cancer cells to chemotherapeutics including front-line drug Doxorubicin. A combination of MsDef1 and Doxorubicin exhibits 5-10-fold greater apoptosis in vitro in MDR triple negative breast cancer (TNBC) cells compared to either MsDef1 or Doxorubicin alone.ConclusionAn antifungal plant defensin MsDef1 is shown to be a cell permeating peptide (CPP) for MDR cancer cells targeted to two tumor specific targets activating two cell death pathways. That makes MsDef1, potentially a tumor targeted sensitizer neoadjuvant to cancer therapy.

From Angiotensin II to Cyclic Peptides and Angiotensin Receptor Blockers (ARBs): Perspectives of ARBs in COVID-19 Therapy

The octapeptide hormone angiotensin II is one of the most studied peptides with the aim of designing and synthesizing non-peptide mimetics for oral administration. To achieve this, cyclizations at different positions within the peptide molecule has been a useful strategy to define the active conformation. These studies on angiotensin II led to the discovery of Sarmesin, a type II angiotensin II antagonist, and the breakthrough non-peptide mimetic Losartan, the first in a series of sartans marketed as a new generation of anti-hypertensive drugs in the 1990s. Angiotensin II receptor blockers (ARBS) and angiotensin I converting enzyme inhibitors (ACEI) were recently reported to protect hypertensive patients infected with SARS-CoV-2. The renin–angiotensin system (RAS) inhibitors reduce excess angiotensin II and increase antagonist heptapeptides alamandine and aspamandine which counterbalance angiotensin II and maintain homeostasis and vasodilation.

C-peptide as a biomarker in preeclampsia

Preeclampsia (PE) is a syndrome exclusive to human pregnancy and responsible for high perinatal morbidity and mortality, whose manifestations include hypertension, proteinuria, and edema. There is evidence that PE incidence is four times higher in diabetic type 1 women than in non-diabetic women; and increases in women with metabolic syndrome and insulin resistance. C-peptide is a 31 amino acid residue polypeptide part of the proinsulin, which is enzymatically cleaved into insulin and C-peptide molecule. Both are simultaneously secreted in equimolar concentrations into blood, thus serum C-peptide level might reflect real insulin production. Little is known about the relationship between circulating levels of C-peptide and the increase in blood pressure in PE. For this reason, we assessed serum levels of C-peptide, and insulin in women with normal pregnancy and with PE, in a population of 30 Venezuelan women. Serum samples were evaluated by multiplex microsphere analysis (Bio-Plex Pro Assays). Our results show increased insulin and C-peptide serum levels in women with PE. Spearman correlation analysis in all subjects showed a positive association between SBP and C-peptide (r= 0.4841; P<0.0251) and insulin (r= 0.4386; P<0.0221), associated with a positive correlation between SBP and proteinuria and glucose. Our results suggest that an increase in C-peptide could be associated with the development of hypertension and insulin resistance in PE. Therefore, the quantification of this peptide could be a promising biomarker to predict the onset of pregnancy-induced hypertension.

Crown ethers as shift reagents in peptide epimer differentiation –conclusions from examination of ac-(H)FRW-NH2 petide sequences

Crown ethers with different ring sizes and substituents (18-crown-6, dibenzo-18-crown-6, dicyclohexano-18-crown-6, a chiral tetracarboxylic acid-18-crown-6 ether, dibenzo-21-crown-7, and dibenzo-30-crown-10) were evaluated as shift reagents to differentiate epimeric model peptides (tri-and tetrapeptides) using ion mobility mass spectrometry (IM-MS). The stable associates of peptide epimers with crown ethers were detected and examined using traveling-wave ion mobility time-of-flight mass spectrometer (Synapt G2-S HDMS) equipped with an electrospray ion source. The overall decrease of the epimer separation upon crown ether complexation was observed. The increase of the effectiveness of the microsolvation of a basic moiety - guanidine or ammonium group in the peptide had no or little effect on the epimer discrimination. Any increase of the epimer separation, which referred to the specific association mode between crown substituents and a given peptide sequence, was drastically reduced for the longer peptide sequence (tetrapeptide). The obtained results suggest that the application of the crown ethers as shift reagents in ion mobility mass spectrometry is limited to the formation of complexes differing in stoichiometry rather than it refers to a specific coordination mode between a crown ether and a peptide molecule.

Synthesis and crystal structure of peptide dimethyl biphenyl hybrid C52H60N6O10·0.25H2O

The synthesis and crystal structure of peptide 6,6′-dimethyl biphenyl hybrid are described. The title compound was synthesized by reaction between 6,6′-dimethyl-[1,1′-biphenyl]-2,2′-dicarbonyl dichloride in CH2Cl2, amine HN–proline–phenylalanine–alanine–COOMe and Et3N at 273 K under N2 atmosphere and characterized by single-crystal X-ray diffraction. The asymmetric unit contains one peptide molecule and a quarter of a water molecule. A disorder of a methyl and methoxycarbonyl group of one alanine residue is observed with occupancy ratio 0.502 (6):0.498 (6). The structure is consolidated by intra- and intermolecular hydrogen bonds.

Magainin as an Antiviral Peptide of SARS-CoV-2 Main Protease for Potential Inhibitor: An In Silico Approach

The new coronavirus (SARS-CoV-2), which caused the global pandemic Coronavirus Disease-2019 (COVID-2019), has infected nearly 206 countries. There is still little information about molecular compounds that can inhibit the development of infections caused by this disease. It is crucial to achieving the discovery of competent natural inhibitor candidates, such as antiviral peptides, because they have a variety of biological activities and have evolved to target biochemical machinery from different pathogens or host cell structures. In silico studies will be carried out, including protein-peptide docking and protein-protein docking, to identify, evaluate, and explore the affinity and molecular interactions of the Magainin-1 and Magainin-2 peptide molecules derived from frog skin (Xenopus laevis) to the main protease macromolecule (Mpro) SARS-CoV-2, and its effect on the ACE-2 receptor (Angiotensin Converting Enzyme-2 Receptor). Protein-peptide docking simulations show that both peptide molecules have a good affinity for the active site area of the SARS-CoV-2 Mpro macromolecule. These results were then confirmed using protein-protein docking simulations to observe the ability of the peptide molecule in preventing attachment to the ACE-2 receptor surface area. In silico studies show that Magainin-2 has the best affinity, with a bond free energy value of −3054.53 kJ/mol. Then the protein-protein docking simulation provided Magainin-2 was able to prevent the attachment of ACE-2 receptors, with an ACE score of 1697.99 kJ/mol. Thus, through in silico research, it is hoped that the Magainin peptide molecule can be further investigated in the development of new antiviral peptides for the treatment of infectious diseases of COVID-19.