GPCRs are omnipresent in the regulation of physiological processes and therefore account for the most prominent drug target class. However, nearly all drugs targeting GPCRs have been developed by the concept of receptors as simple on-off switches. This is surprising, because specifically addressing a distinct intracellular signaling pathway holds the potential to develop safer and more efficient drugs. In recent years more and more ligands have been reported that shift the naturally imprinted preference of a receptor’s signaling profile, so-called biased ligands. It has been demonstrated for several aminergic GPCRs that an extension of their molecular structure towards extracellular receptor regions results in biased signaling. The underlying mechanism is a specific interference with the allosteric coupling mechanism by which extra- and intracellular sides of the receptor are conformationally linked. We propose a potential blueprint for the design of biased ligands based on the concept of specific interference with the extracellular receptor region and a restriction of its conformational space by extended ligand structures. While this design concept will likely identify new biased ligands, it remains a challenge to specifically design ligands with a desired signaling profile.

Sida linifolia L., a common weed found in dry forest areas in West Africa and other parts of the world, is associated with several folkloric applications in Africa, including its use in assuaging painful whitlows and in malaria management; however, scanty or no scientific study has validated its bioactivities. Herein, we investigated the anti-nociceptive and anti-inflammatory mechanisms of ethanolic (ELFSL) and ethyl acetate (EALFSL) fractions of Sida linifolia leaves. The in vivo anti-inflammatory activities were evaluated by edema induction with an intraperitoneal injection of freshly prepared carrageenan (0.1 ml of 0.01 g/ml) and 0.1 ml of undiluted fresh egg albumin into mice's hind paw, while hind paw licking and writhing were induced in mice using formalin (i.p.) (0.02 ml of 1 % v/v) and 0.6 % (v/v) (10 ml/kg bw) (i.p.) acetic acid, respectively, to assay for the anti-nociceptive potentials. Varying amounts of flavonoids, tannins, and other phenols, terpenoids, saponins, steroids, and alkaloids were detected in the fractions. The LD₅₀ study showed no toxicity up to 5000 mg/kg body weight (per oral) EALFSL and ELFSL. Interestingly, oral administration of various concentrations (200, 400 and 600 mg/kg bw) of the fractions significantly (P < 0.05) inhibited all phases of edemogenesis, mice's hind licking, and writhing compared with control and were comparable with 100 mg/kg bw (p.o.) aspirin. However, ELFSL showed significantly (P > 0.05) better anti-nociceptive and anti-inflammatory activities than EAFSL. These suggest that leaf fractions of Sida linifolia possess anti-inflammatory and anti-nociceptive potentials, possibly mediated by peripheral and central mechanisms.

Antimicrobial peptides (AMPs) are naturally occurring host defense molecules, representing an evolutionarily ancient innate immune mechanism against pathogenic infection. As such, many of these
predominantly cationic and amphipathic peptides have been examined for their potential as anti-infective
agents. AMP families such as the defensins and cathelicidins exhibit broad-spectrum antimicrobial activity
against a wide variety of bacteria, fungi and viruses, predominantly by disruption of the microbial
membrane. Due to this physical mechanism, development of resistance by the pathogen is rare. Thus, they
represent a great potential for a new type of anti-infective agent. However, due to a variety of reasons,
including protease sensitivity and poor bioavailability, they have not been developed into actual
therapeutics. To circumvent these issues, we have examined the potential for small molecule mimetics of
AMPs, which would be protease resistant, and have better bioavailability. We previously demonstrated
activity of one such class of mimetics, sequence-specific N-substituted glycine oligomers, or peptoids,
against the human viral pathogen Herpes Simplex Virus-1 (HSV-1), as well as some bacteria. Here we
compare the activity, both in vitro and in vivo, of select peptoids against bacteria, fungi and viruses, to
begin to study the structure/activity relationship with a broad spectrum of microbial pathogens. Our
results show that some peptoid structures are more active against one type of pathogen than another.
However, at least two of the tested peptoids exhibit potent activity against Gram+ bacteria, Grambacteria,
fungi and viruses. Our result suggest that these molecules can be developed into potent broadspectrum
antimicrobial agents.

Lurasidone hydrochloride is a second-generation (atypical) antipsychotic agent who is used for the treatment of schizophrenia and bipolar depression. The mechanism of action of lurasidone is not completely elucidated, assumed to affect dopamine and serotonin receptors, but is devoid of antihistaminic or anticholinergic activities [1].

Human serum albumin (HSA), the most abundant transport protein in blood plasma, consisting of 585 aminoacids residues and have three binding sites (I, II and III) [2,3]. The most of drugs binds to hydrophobic cavities in subdomains IIA and IIIA, in the site I and II, respetively. Investigation the interactions of drugs to HSA may give useful informations of effectiveness of drugs.

In this study, we investigate interactions between lurasidone and human serum albumin (HSA) by the fluorescence quenching technique, synchronous fluorescence spectroscopy and molecular docking.

The objects of the present study are nanoparticles (NPs) based on a copolymer of lactic and glycolic acids (PLGA), loaded with the anticancer drug doxorubicin (DOX-NP) and histone deacetylase inhibitor vorinostat (SAHA-NP), developed for the breast cancer treatment. Drug encapsulation into PLGA matrix improve drug safety profile and allow to overcome multidrug resistance. In the current study, we developed a high-performance liquid chromatography method for the simultaneous determination of DOX-NP and SAHA-NP using Box-Behnken design, followed by the validation and NPs stability determination after sterilization treatment with γ-irradiation.

The separation was performed using a Nucleodur C-18 Gravity column (250 mm × 4.6 mm × 5 µm). Samples were prepared by precipitating PLGA with dimethyl sulfoxide. Three independent variables were analyzed to determine the most optimal conditions: methanol concentration (0-20%), pH (2.5-4.5) and flow rate (0.8 -1.2 mL /min). We evaluated contributions of these variables to the peak resolution and the retention time of the last peak of the analyte using Box-Behnken design. Next, we simultaneously optimized all dependent variables and established their most optimal values using the desirability function.

The optimized method was accurate, precise and linear in the range of 4.2–52.0 µg/mL for both drugs (R² = 0.9999 for vorinostat and R² = 0.9988 for doxorubicin). γ-irradiation at a dose of 25 kGy resulted in degradation of DOX-NP less than 95%, while the amount of SAHA-NP impurities was 88%.

Thus, the developed method is suitable for simultaneous analysis of DOX-NP and SAHA-NP, including the analysis of impurities.

Funding: This study was supported by the Russian Science Foundation research grant No. 22-25-00293, https://rscf.ru/project/22-25-00293/

The use of p53-MDM2/X inhibitors is a prospective strategy in anti-cancer therapy for tumors with wild type p53 protein. In our study new low molecular weight inhibitors of p53-mdm2 interaction have been proposed. The two-step synthesis of the imidazoline core with subsequent modifications for the nitrogen atom was carried out. New molecules cause the accumulation of p53 protein levels more than 7 times in comparison with the control. The accumulation of proapoptotic proteins such as p21, PUMA has also been investigated, and the mechanism of cell death has been shown.

Modification of capsule shells with the synthesized magnetic iron oxide nanoparticles aims not only to control the localization of capsules, but also to tune their permeability. Application of a super low frequency nonheating magnetic field (< 100 Hz) for these purposes offer prospects of high penetration ability into tissues, high locality and safety, which makes this method more preferable for using in vivo than magnetic hyperthermia. In this work, we develop a proof of concept for remotely controlled release of an encapsulated drug from polyelectrolyte microcapsules under the exposure to an alternating super low frequency magnetic field.

The characteristics of the tailor-made nanoparticles for the polyelectrolyte shell modification were analyzed to confirm their perspectives as magneto-mechanical actuators due to their ability to the Brownian relaxation. Polyelectrolyte microcapsules were obtained by the well known method of sequential deposition of polyelectrolytes on the surface of vaterite particles. We studied the time dependence of the amount of released fluorescently labeled high-molecular weight substance on the frequency of the applied magnetic field (100 mT, 20-100 Hz), and demonstrated that the application of a magnetic field with a frequency of 50 Hz leads to the most pronounced selective increase in the permeability of the shells. Our findings provide a promising application of composite magnetic microcapsules with permeability triggered by a super low frequency magnetic field for controlled release of drugs without dangerous heating and overheating of the biological tissues.

The work supported by the grant of the President of the Russian Federation (MK-1109.2021.1.3).

Series of calcium carbonate particles with sizes of 500 ± 80 nm and 200±90 were obtained by the mass crystallization in aqueous salt solutions by varying the reaction conditions and adding glycerol or combination of polyethylene glycol, polysorbat-80 and cell cultural medium to the reaction volume. Calcium carbonate nanoparticles of 50±30 nm in diameter were synthesized within the pores of mesoporous silica particles with a subsequent etching out of the template material. A complete characterization of the particles was carried out using scanning and transmission electron microscopy, X-ray powder diffraction, dynamic and electrophoretic light scattering. CaCO3 particles were loaded with anticancer drugs, porphyrazine and doxorubicin, with an encapsulation efficiency of 2-5 and 4-11 wt.%, respectively. The spontaneous release at pH 7 reached 15%, and when the particles are dissolved at pH 4, the release was about 45% of the substance during the day, regardless of the encapsulated substance. Functionalization of the surface of calcium carbonate particles with a biocompatible Pluronic-folic acid conjugate did not affect the particle size distribution and aggregative stability for all three samples. The effect of coatings on the rate of internalization and accumulation of particles by cells expressing folic acid receptors was established. It was also shown that the internalization of 50 ± 30 nm particles was more active than other samples.

The work supported by the Russian Science Foundation (Project #21-74-10058).

Seborrheic dermatitis (SD) is the most common dermatological disease in more than 50% of the population all over the world. Malassezia species are lipophilic yeasts that cause seborrheic dermatitis and dandruff in humans. The treatment of SD is mainly based on azole antifungal drugs that are targeted against biosynthesis of sterols. But these chemicals have poor compliance, emerging resistance, and low bioavailability. Interestingly, Malassezia species secrete several lipases that are responsible of the production of fatty acids and inflammatory cytokines. Novel synthetic and natural agents act on lipase but has low solubility and bioavailability. β-cyclodextrin (β-CD) as an additive has attracted attention for enhance solubility and drug delivery. Therefore, the aim of study was evaluation of β-CD influence on lipase structure and enzymatic activity for hydrolysis of acylglycerides by lipase. Modern methods as UV-spectroscopy, fluorescence assay and electron microscopy with TEM were used. The results showed that lipase could decrease yield of oleic acid in presence of β-CD. The UV spectroscopy and fluorescence assay demonstrated that the absorbance and fluorescence of lipase decreased with increasing concentration of β-CD due to surface interaction and change of enzyme configuration. Moreover, electron microscopy with TEM showed that lipase formed a special conglomerate with β-CD for changing hydrolysis that can be useful for drug delivery of lipase inhibitors. Overall results indicate that β-CD could change enzymatic activity of the lipase and can be considered as promising carrier for drug delivery of lipase inhibitors.

Selective modification of natural compounds is one of the most important ways to develop and search for new biologically active substances of various structural types.

It was found earlier that some compounds with octahydro-2H-chromene scaffolds synthesized from monoterpenoid (-)-isopulegol demonstrated promising biological activity, e.g., analgesic, and antiviral activities, inhibitory activity against DNA repair enzyme Tdp1.

The flexible method for the synthesis of octahydro-2H-chromenes derivatives is the Prins cyclization. This reaction could serve also as an initiator of a three-component tandem reaction. For example, the sequence of the Prins and Ritter reactions is one of the best synthetic methods to efficiently build six-membered fragment of 4-amidotetrahydropyran in a one-pot single step reaction.

In this work we have developed a method for synthesis of chiral 4-acetamido-octahydro-2H-chromenes. We used tandem Prins-Ritter reaction between (-)-isopulegol and a set of ketones in acetonitrile. Desired products were formed as a mixture of 4R/4S diastereomers, where 4S one is a major isomer.

Development of new analgesic agents with high activity and low toxicity is important task. It is known that the heterocyclic compounds synthesized from (–)-isopulegol exhibit analgesic activity. In the study of the analgesic activity of the synthesized compounds in vivo, we found that a number of derivatives showed high analgesic activity reliably and not inferior in efficiency to the reference drug sodium diclofenac administered at a similar dose.