Design of a Synthetic Long Peptide Vaccine Targeting HPV-16 and -18 Using Immunoinformatic Methods.

Human papillomavirus types 16 and 18 cause the majority of cervical cancers worldwide. Despite the availability of three prophylactic vaccines based on virus-like particles (VLP) of the major capsid protein (L1), these vaccines are unable to clear an existing infection. Such infected persons experience an increased risk of neoplastic transformation. To overcome this problem, this study proposes an alternative synthetic long peptide (SLP)-based vaccine for persons already infected, including those with precancerous lesions. This new vaccine was designed to stimulate both CD8+ and CD4+ T cells, providing a robust and long-lasting immune response. The SLP construct includes both HLA class I- and class II-restricted epitopes, identified from IEDB or predicted using NetMHCPan and NetMHCIIPan. None of the SLPs were allergenic nor toxic, based on in silico studies. Population coverage studies provided 98.18% coverage for class I epitopes and 99.81% coverage for class II peptides in the IEDB world population's allele set. Three-dimensional structure ab initio prediction using Rosetta provided good quality models, which were assessed using PROCHECK and QMEAN4. Molecular docking with toll-like receptor 2 identified potential intrinsic TLR2 agonist activity, while molecular dynamics studies of SLPs in water suggested good stability, with favorable thermodynamic properties.

Therapeutic Properties of Several Chemical Compounds of Salvia officinalis L. in Alzheimer's Disease.

BACKGROUND: Currently, the pharmacological management of Alzheimer's disease is based on several chemical structures, represented by acetylcholinesterase and N-methyl-D-aspartate (NMDA) receptor ligands, with still unclear molecular mechanisms and severe side effects. For this reason, a challenge for Alzheimer's disease treatment remains to identify new drugs with reduced side effects. Recently, the natural compounds, particularly, certain chemical compounds identified in the essential oil of peppermint, sage, grapes, sea buckthorn, have increased interest as possible therapeutics. OBJECTIVES: In this paper, we have summarized data from the recent literature on several chemical compounds extracted from Salvia officinalis L., with therapeutic potential in Alzheimer's disease. METHODS: In addition to the wide range of experimental methods performed in vivo and in vitro, we also presented some in silico studies of medicinal compounds. RESULTS: Through this mini-review, we presented the latest information regarding the therapeutic characteristics of natural compounds isolated from Salvia officinalis L. in Alzheimer's disease. CONCLUSION: Thus, based on the information presented, we can say that phytotherapy is a reliable therapeutic method in a neurodegenerative disease.

In Silico and In Vitro Experimental Studies of New Dibenz[b,e]oxepin-11(6H)one O-(arylcarbamoyl)-oximes Designed as Potential Antimicrobial Agents.

In a drug-repurposing-driven approach for speeding up the development of novel antimicrobial agents, this paper presents for the first time in the scientific literature the synthesis, physico-chemical characterization, in silico analysis, antimicrobial activity against bacterial and fungal strains in planktonic and biofilm growth state, as well as the in vitro cytotoxicity of some new 6,11-dihydrodibenz[b,e]oxepin-11(6H)one O-(arylcarbamoyl)oximes. The structures of intermediary and final substances (compounds 7a-j) were confirmed by 1H-NMR, 13C-NMR and IR spectra, as well as by elemental analysis. The in silico bioinformatic and cheminformatic studies evidenced an optimal pharmacokinetic profile for the synthesized compounds 7a-j, characterized by an average lipophilic character predicting good cell membrane permeability and intestinal absorption; low maximum tolerated dose for humans; potassium channels encoded by the hERG I and II genes as potential targets and no carcinogenic effects. The obtained compounds exhibited a higher antimicrobial activity against the planktonic Gram-positive Staphylococcus aureus and Bacillus subtilis strains and the Candida albicans fungal strain. The obtained compounds also inhibited the ability of S. aureus, B. subtilis, Escherichia coli and C. albicans strains to colonize the inert substratum, accounting for their possible use as antibiofilm agents. All the active compounds exhibited low or acceptable cytotoxicity levels on the HCT8 cells, ensuring the potential use of these compounds for the development of new antimicrobial drugs with minimal side effects on the human cells and tissues.

Design, Synthesis and In Vitro Characterization of Novel Antimicrobial Agents Based on 6-Chloro-9H-carbazol Derivatives and 1,3,4-Oxadiazole Scaffolds.

In this paper, we aimed to exploit and combine in the same molecule the carbazole and the 1,3,4-oxadiazole pharmacophores, to obtain novel carprofen derivatives, by using two synthesis pathways. For the first route, the following steps have been followed: (i) (RS)-2-(6-chloro-9H-carbazol-2-yl)propanonic acid (carprofen) treatment with methanol, yielding methyl (RS)-2-(6-chloro-9H-carbazol-2-yl)propanoate; (ii) the resulted methylic ester was converted to (RS)-2-(6-chloro-9H-carbazol-2-yl)propane hydrazide (carprofen hydrazide) by treatment with hydrazine hydrate; (iii) reaction of the hydrazide derivative with acyl chlorides led to N-[(2RS)-2-(6-chloro-9H-carbazol-2-yl)propanoil]-N'-R-substituted-benzoylhydrazine formation, which; (iv) in reaction with phosphorus oxychloride gave the (RS)-1-(6-chloro-9H-carbazol-2-yl)-1-(1,3,4-oxadiazol-2-yl)ethane derivatives. In the second synthesis pathway, new 1,3,4-oxadiazole ring compounds were obtained starting from carprofen which was reacted with isoniazid, in the presence of phosphorus oxychloride to form (RS)-1-(6-chloro-9H-carbazol-2-yl)-1-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]ethane. The synthesized compounds were characterized by IR, 1H-NMR and 13C-NMR, screened for their drug-like properties and evaluated for in vitro cytotoxicity and antimicrobial activity. The obtained compounds exhibited a good antimicrobial activity, some of the compounds being particularly active on E. coli, while others on C. albicans. The most significant result is represented by their exceptional anti-biofilm activity, particularly against the P. aeruginosa biofilm. The cytotoxicity assay revealed that at concentrations lower than 100 µg/mL, the tested compounds do not induce cytotoxicity and do not alter the mammalian cell cycle. The new synthesized compounds show good drug-like properties. The ADME-Tox profiles indicate a good oral absorption and average permeability through the blood brain barrier. However, further research is needed to reduce the predicted mutagenic potential and the hepatotoxicity.