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Abstract 70 kDa heat shock protein Hsp70 (also termed HSP70A1A) is the major stress-inducible member of the HSP70 chaperone family, which is present on the plasma membranes of various tumor cells, but not on the membranes of the corresponding normal cells. The exact mechanisms of Hsp70 anchoring in the membrane and its membrane-related functions are still under debate, since the protein does not contain consensus signal sequence responsible for translocation from the cytosol to the lipid bilayer. The present study was focused on the analysis of the interaction of recombinant human Hsp70 with the model phospholipid membranes. We have confirmed that Hsp70 has strong specificity toward membranes composed of negatively charged phosphatidylserine (PS), compared to neutral phosphatidylcholine membranes. Using differential scanning calorimetry, we have shown for the first time that Hsp70 affects the thermotropic behavior of saturated PS and leads to the interdigitation that controls membrane thickness and rigidity. Hsp70-PS interaction depended on the lipid phase state; the protein stabilized ordered domains enriched with high-melting PS, increasing their area, probably due to formation of quasi-interdigitated phase. Moreover, the ability of Hsp70 to form ion-permeable pores in PS membranes may also be determined by the bilayer thickness. These observations contribute to a better understanding of Hsp70-PS interaction and biological functions of membrane-bound Hsp70 in cancer cells.

Polyene antibiotics have been used in antifungal therapy since the mid-twentieth century. They are highly valued for their broad spectrum of activity and the rarity of pathogen resistance to their action. However, their use in the treatment of systemic mycoses often results in serious side-effects. Recently, there has been a renewed interest in the development of new antifungal drugs based on polyenes, particularly due to the emergence of highly dangerous pathogenic strains of fungi, such as Candida auris, and the increased incidence of mucormycosis. Considerable understanding has been established regarding the structure–biological activity relationships of polyene antifungals. Yet, no previous studies have examined the effect of introducing quaternized fragments into their molecular structure. In this study, we present a series of amides of amphotericin B, nystatin, and natamycin bearing a quaternized group in the side chain, and discuss their biological properties: antifungal activity, cytotoxicity, and effects on lipid bilayers that mimic fungal and mammalian cell membranes. Our research findings suggest that the nature of the introduced quaternized residue plays a more significant role than merely the introduction of a constant positive charge. Among the tested polyenes, derivatives 4b, 5b, and 6b, which contain a fragment of N-methyl-4-(aminomethyl)pyridinium in their structure, are particularly noteworthy due to their biological activity.

Polyene antifungal amphotericin B (AmB) has been used for over 60 years, and remains a valuable clinical treatment for systemic mycoses, due to its broad antifungal activity and low rate of emerging resistance. There is no consensus on how exactly it kills fungal cells but it is certain that AmB and the closely-related nystatin (Nys) can form pores in membranes and have a higher affinity towards ergosterol than cholesterol. Notably, the high nephro- and hemolytic toxicity of polyenes and their low solubility in water have led to efforts to improve their properties. We present the synthesis of new amphotericin and nystatin amides and a comparative study of the effects of identical modifications of AmB and Nys on the relationship between their structure and properties. Generally, increases in the activity/toxicity ratio were in good agreement with increasing ratios of selective permeabilization of ergosterol- vs. cholesterol-containing membranes. We also show that the introduced modifications had an effect on the sensitivity of mutant yeast strains with alterations in ergosterol biosynthesis to the studied polyenes, suggesting a varying affinity towards intermediate ergosterol precursors. Three new water-soluble nystatin derivatives showed a prominent improvement in safety and were selected as promising candidates for drug development.

This article offers a new interpretation of Boris Pasternak’s novel Doctor Zhivago in the cultural and historical context of the first half of the 20th century, with an emphasis on the interrelationship between religion and philosophy of history in the text. Doctor Zhivago is analysed as a condensed representation of a religious conception of Russian history between 1901 and 1953 and as a cyclical repetition of the Easter narrative. This bipartite narrative consists of the Passion and Resurrection of Christ as symbols of violence and renewal (liberation). The novel cycles through this narrative several times, symbolically connecting the ‘Easter’ revolution (March 1917) and the Thaw (the spring of 1953). The sources of Pasternak’s Easter narrative include the Gospels, Leo Tolstoy’s philosophy of history and pre-Christian mythology. The model of cyclical time in the novel brings together the sacred, natural and historical cycles. This concept of a cyclical renewal of life differs from the linear temporality of the Apocalypse as an expectation of the end of history.