RNA-targeting Therapy: A Promising Approach to Reach Non-Druggable Targets

The term "non-druggable" refers to a protein that cannot be targeted pharmacologically; recently, significant efforts have been made to convert these proteins into targets that are reachable or "druggable." Pharmacologically targeting these difficult proteins has emerged as a major challenge in modern drug development, necessitating the innovation and development of new technologies. The idea of using RNA-targeting therapeutics as a platform to reach unreachable targets is very appealing. Antisense oligonucleotides, nucleic acid or aptamers, RNA interference therapeutics, microRNA, and synthetic RNA are examples of RNA-targeting therapeutics. Many of these agents were FDA-approved for the treatment of rare or genetic diseases, as well as molecular markers for disease diagnosis. As a promising type of therapeutic, many studies are being conducted in order for more and more of them to be approved and used in different disease treatments and to shift them from treating rare diseases only to being used as more specific targeting agents in the treatment of various common diseases. This article will look at some of the most recent technological and pharmaceutical advances that have contributed to the erosion of the concept of undruggability.

Withaferin A: From Ancient Remedy to Potential Drug Candidate

Withaferin A (WA) is a pivotal withanolide that has conquered a conspicuous place in research, owning to its multidimensional biological properties. It is an abundant constituent in Withania somnifera Dunal. (Ashwagandha, WS) that is one of the prehistoric pivotal remedies in Ayurveda. This article reviews the literature about the pharmacological profile of WA with special emphasis on its anticancer aspect. We reviewed research publications concerning WA through four databases and provided a descriptive analysis of literature without statistical or qualitative analysis. WA has been found as an effective remedy with multifaceted mechanisms and a broad spectrum of pharmacological profiles. It has anticancer, anti-inflammatory, antiherpetic, antifibrotic, antiplatelet, profibrinolytic, immunosuppressive, antipigmentation, antileishmanial, and healing potentials. Evidence for wide pharmacological actions of WA has been established by both in vivo and in vitro studies. Further, the scientific literature accentuates the role of WA harboring a variable therapeutic spectrum for integrative cancer chemoprevention and cure. WA is a modern drug from traditional medicine that is necessary to be advanced to clinical trials for advocating its utility as a commercial drug.

The use of plant fibers for oligosaccharide production with libraries constructed by combinatorial enzyme technology

: Combinatorial chemistry involves the chemical or biological synthesis of libraries of the diverse structural population of a template molecule and the screening for the variants expressing desirable target properties. The approach has been a focus of research activity in modern drug discovery and biotechnology for accelerating the discovery and development of novel therapeutic and bioactive compounds. This review describes the application of combinatorial chemistry in enzyme technology as a novel technique and invention developed in our laboratory to construct oligosaccharide libraries in the conversion of plant fibers. The theory, mechanism, development, and application of this combinatorial enzyme approach are presented for the first time. The potential food and non-food uses of oligosaccharides are described. Citrus pectin and wheat insoluble fiber have been used as substrates for combinatorial enzyme reactions. Generation of libraries of structural variants of pectic oligosaccharides (oligoGalA) and feruloyl oligosaccharides (FOS) demonstrates the feasibility and usefulness of the technique in the transformation of plant biomass to value-added products.

Comparing Antibiotic Pastes with Electrospun Nanofibers as Modern Drug Delivery Systems for Regenerative Endodontics

: Nanomaterials have various features that make these types of materials able to be applied in different biomedical applications like, diagnosis, treatment, and drug delivery. Using such materials in endodontic filed both to face the challenges that occur during treatment processes and to make these materials have an antibacterial effect without showing any harm on the host cells. The approach of nanofibers loaded with various antibacterial drugs offers a potential treatment method to enhance the elimination procedure of intracanal biofilms. Clinically, many models of bacterial biofilms have been prepared under in vitro conditions for different aims. The process of drug delivery from polymeric nanofibers is based on the principle that the releasing ratio of drug molecules increases due to the increase in the surface area of the hosted structure. In our review, we discuss diverse approaches of loading/releasing drugs on/from nanofibers and we summarized many studies about electrospun nanofibers loaded various drugs applied in the endodontic field. Moreover, we argued both the advantages and the limitations of these modern endodontic treatment materials comparing them with the traditional ones.

TeachOpenCADD 2021: Open Source and FAIR Python Pipelines to Assist in Structural Bioinformatics and Cheminformatics Research

Computational pipelines have become a crucial part of modern drug discovery campaigns. Setting up and maintaining such pipelines, however, can be challenging and time-consuming --- especially for novice scientists in this domain. TeachOpenCADD is a platform that aims to teach domain-specific skills and to provide pipeline templates as starting points for research projects. We offer Python-based solutions for common tasks in cheminformatics and structural bioinformatics in the form of Jupyter notebooks and based on open source resources only. Including the 12 newly released additions, TeachOpenCADD now contains 22 notebooks that each cover both theoretical background as well as hands-on programming. To promote reproducible and reusable research, we apply software best practices to our notebooks such as testing with an automated continuous integration and adhering to a more idiomatic Python style. The new TeachOpenCADD website is available at https://projects.volkamerlab.org/teachopencadd and all code is deposited on GitHub.

Isolated chemohyperthermal perfusion of the liver with melphalan in the treatment of unresectable liver metastases with uveal melanoma

Uveal melanoma belongs to rare malignant neoplasms, and the biological peculiarity of this tumor determines the high rate of distant metastasis, which reaches 60 %. Most frequently, uveal melanoma metastases are localized in the liver and have an isolated character. At the same time, despite the achievements of modern drug therapy, the treatment results of this category of patients remain unsatisfactory. Among the regional methods of treatment of metastatic uveal melanoma, surgical treatment is considered to be the most effective. Median survival rate in the group of radically operated patients (R0) is 27 months. At present, in the vast majority of cases, surgical treatment is impossible because of multiple bilobar metastasis and advanced cancer process. Median life expectancy of patients with liver metastases is only 9 months. A promising method of regional treatment of inoperable metastatic uveal melanoma is isolated liver chemoperfusion. Multidisciplinary team of Radiology Scientific Research Center and Kostroma Oncologic Dispensary for the first time in Russia presents a clinical case of a patient with isolated inoperable uveal melanoma liver metastases using an innovative method - isolated high-dose chemo hyperthermic liver perfusion with melphalan. The article describes in detail the method of the procedure, estimates immediate (partial response in 1 month after the procedure) and long-term results of the method (stabilization of the condition against the background of immunotherapy in 9 months after surgery). Based on the presented clinical observation, isolated liver chemoperfusion with melphalan for this category of patients is reasonable. However, despite the encouraging immediate results, clinical experience needs to be accumulated in order to be further evaluated in clinical trials.

Merging Directed C−H Activations with High-Throughput Experimentation: Development of Predictable Iridium-Catalyzed C−H Aminations Applicable to Late-Stage Functionalization

Herein, we report an iridium-catalyzed directed C−H amination methodology developed using a high-throughput experimentation (HTE)-based strategy, applicable for the needs of automated modern drug discovery. The informer library approach for investigating accessible directing group chemical space for the reaction, in combination with functional group tolerance screening and substrate scope investigations, allowed for the generation of an empirical predictive model to guide future users. Applicability to late-stage functionalization of complex drugs and natural products, in combination with multiple deprotection protocols leading to the desirable aniline matched pairs, serve to demonstrate the utility of the method for drug discovery. Finally reaction miniaturization to a nano molar range highlights the opportunities for more sustainable screening with decreased material consumption.

The SGLT-2 Inhibitors in Personalized Therapy of Diabetes Mellitus Patients

Diabetes mellitus (DM) represents a major public health problem, with yearly increasing prevalence. DM is considered a progressive vascular disease that develops macro and microvascular complications, with a great impact on the quality of life of diabetic patients. Over time, DM has become one of the most studied diseases; indeed, finding new pharmacological ways to control it is the main purpose of the research involved in this issue. Sodium–glucose cotransporter 2 inhibitors (SGLT-2i) are a modern drug class of glucose-lowering agents, whose use in DM patients has increased in the past few years. Besides the positive outcomes regarding glycemic control and cardiovascular protection in DM patients, SGLT-2i have also been associated with metabolic benefits, blood pressure reduction, and improved kidney function. The recent perception and understanding of SGLT-2i pathophysiological pathways place this class of drugs towards a particularized patient-centered approach, moving away from the well-known glycemic control strategy. SGLT-2i have been shown not only to reduce death from cardiovascular causes, but also to reduce the risk of stroke and heart failure hospitalization. This article aims to review and highlight the existing literature on the effects of SGLT-2i, emphasizing their role as oral antihyperglycemic agents in type 2 DM, with important cardiovascular and metabolic benefits.