[Development of a Series of Neutralizing Nanobodies against SARS-CoV-2 Spike Protein].

Countering the spread of new respiratory infections and reducing the damage they cause to society requires efficient strategies for rapidly developing of targeted therapeutics, such as monoclonal antibodies. Nanobodies, defined as variable fragments of heavy-chain camelid antibodies, have a set of characteristics that make them particularly convenient for this purpose. The speed at which the SARS-CoV-2 pandemic spread confirmed that the key factor in the development of therapeutics is obtaining highly effective blocking agents as soon as possible, as well as the diversity of epitopes to which these agents bind. We have optimized the selection process of blocking nanobodies from the genetic material of camelids and obtained a panel of nanobody structures with affinity to Spike protein in the lower nanomolar and picomolar ranges and with high binding specificity. The subset of nanobodies that demonstrate the ability to block the interaction between the Spike protein and the cellular ACE2 receptor was selected in experiments in vitro and in vivo. It has been established that the epitopes bound by the nanobodies are located in the RBD domain of the Spike protein and have little overlap. The diversity of binding regions may allow a mixture of nanobodies to retain potential therapeutic efficacy towards new Spike protein variants. Furthermore, the structural features of nanobodies, particularly their compact size and high stability, indicate the possibility of their utilization in the form of aerosols.

[CD47 receptor as a primary target for cancer therapy].

Recently, a number of new highly efficient antibody-based anticancer therapeutics have emerged. These receptor-binding antibodies have beneficial toxicity profiles associated with relatively mild side effects. Therefore, the search for novel surface proteins that are present on cancer cells and play important metabolic or defensive roles has intensified. Additionally, the therapeutic stimulation of patient's immune system in order to aim its components, specifically, phagocytes and cytotoxic T-lymphocytes, at tumor cells is gaining traction. This review is focused on the CD47 surface receptor, a ubiquitously expressed molecule, which could nevertheless serve as a therapeutic target due to its ability to simultaneously stimulate both natural and adaptive immune response.

[Role of PDLIM4 and c-Src in Breast Cancer Progression].

High heterogeneity is characteristic of oncology diseases, often complicating the choice of optimal anticancer treatment. One cancer type may combine tumors differing in histogenesis, genetic lesions, and mechanism of cell transformation. Differences in the mechanism of cell malignant transformation result in specifics of cancer cell metabolism and sensitivity to various agents, including anticancer treatments. Hence, the molecular subtype of a tumor is essential to know for choosing the optimal therapeutic strategy. The review considers the role actin-associated proteins and tyrosine kinases, in particular, PDLIM4 and Src kinase, play in the formation of pathological signaling pathways.

[Oncotoxic proteins in cancer therapy: mechanisms of action].

Cancer therapeutics based on protein biomolecules that exhibit selective toxic of inhibiting effects towards tumor cells without affecting normal tissue, are gaining extensive attention in cancer research. This heterogenous group of proteins consists of several subgroups, among them, are engineered cancer antigen-specific antibodies that suppress tumor growth by blocking proliferation-inducing receptors, or by direct action of a covalently attached toxin. Another subgroup of anticancer proteins that also represents promising potential therapeutic agents is oncotoxic proteins that can selectively trigger proapoptotic signaling in cancer cells. The oncotoxic proteins target such commonly disturbed processes in tumor calls as enhanced cell proliferation, altered cell-cycle control, deficient apoptotic response, inhibited mitochondrial respiration and activated glycolysis. The introduction of oncotoxic proteins to the clinic might substantially widen and upgrade modern arsenal of anticancer therapeutics.

Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway.

Identification of unique features of cancer cells is important for defining specific and efficient therapeutic targets. Mutant p53 is present in nearly half of all cancer cases, forming a promising target for pharmacological reactivation. In addition to being defective for the tumor-suppressor function, mutant p53 contributes to malignancy by blocking a p53 family member p73. Here, we describe a small-molecule RETRA that activates a set of p53-regulated genes and specifically suppresses mutant p53-bearing tumor cells in vitro and in mouse xenografts. Although the effect is strictly limited to the cells expressing mutant p53, it is abrogated by inhibition with RNAi to p73. Treatment of mutant p53-expressing cancer cells with RETRA results in a substantial increase in the expression level of p73, and a release of p73 from the blocking complex with mutant p53, which produces tumor-suppressor effects similar to the functional reactivation of p53. RETRA is active against tumor cells expressing a variety of p53 mutants and does not affect normal cells. The results validate the mutant p53-p73 complex as a promising and highly specific potential target for cancer therapy.