Current Medicinal Chemistry (v.24, #18)

Highlights in Endocytosis of Nanostructured Systems by Aline R. Voltan, Kaila M. Alarcon, Ana M. Fusco-Almeida, Christiane P. Soares, Maria J. S. Mendes-Giannini, Marlus Chorilli (1909-1929).
The focus of this review is the cellular internalisation mechanism of nanostructured systems (NSs) and their endosomal escape for targeted drug delivery. Endocytosis is a cellular process of internalisation of different molecules and foreign microorganisms. It is currently being studied for drug delivery through nanostructured systems. The most commonly studied routes of cellular uptake are phagocytosis, macro-pinocytosis, clathrinmediated endocytosis, caveolin-mediated endocytosis, and clathrin and caveolinindependent endocytosis. The mechanism utilised by NSs for cellular entry depends on factors such as cell type and its physicochemical properties. Currently, with the development of drugs-loaded onto NSs, it has been possible to increase the therapeutic index against few diseases. The NSs can deliver the active drug at locations that conventional drugs cannot, thereby minimising unwanted side effects. On cellular entry of NSs, there is a possibility of an endosomal escape of the contents into the cytoplasm, a mechanism that can be exploited so that NSs can migrate intra-cellularly and deliver the drug to the target of interest. Designing endolysosomal escape strategy is not an easy task, but it is critical for the optimal pharmacological action on the target tissue. The cellular uptake of drugs is a very important factor in therapy. Although NSs have emerged as effective drug delivery vehicle for treatment of diseases, it is crucial to understand the mechanism of NSs endocytosis.

Displacement of Drugs from Human Serum Albumin: From Molecular Interactions to Clinical Significance by Hrvoje Rimac, Željko Debeljak, Mirza Boji|, Larisa Miller (1930-1947).
Background: Human serum albumin (HSA) is the most abundant protein in human serum. It has numerous functions, one of which is transport of small hydrophobic molecules, including drugs, toxins, nutrients, hormones and metabolites. HSA has the ability to interact with a wide variety of structurally different compounds. This promiscuous, nonspecific affinity can lead to sudden changes in concentrations caused by displacement, when two or more compounds compete for binding to the same molecular site.

Objective: It is important to consider drug combinations and their binding to HSA when defining dosing regimens, as this can directly influence drug's free, active concentration in blood.

Conclusion: In present paper we review drug interactions with potential for displacement from HSA, situations in which they are likely to occur and their clinical significance. We also offer guidelines in designing drugs with decreased binding to HSA.

Novel Antibacterial Compounds and their Drug Targets - Successes and Challenges by Agnieszka A. Kaczor, Andrzej Polski, Karolina Sobótka-Polska, Anna Pachuta-Stec, Magdalena Makarska-Bialokoz, Monika Pitucha (1948-1982).
Infectious diseases are one of the most important and urgent health problems in the world. According to the World Health Organization (WHO) statistics, infectious and parasitic diseases are a cause of about 16% of all deaths worldwide and over 40% of deaths in Africa. A considerable progress that has been made during last hundred years in the fight against infectious diseases, in particular bacterial infections, can be attributed mainly to three factors: (1) the general improvement of living conditions, in particular sanitation; (2) development of vaccines and (3) development of efficient antibacterial drugs. Although considerable progress in reduction of the number of cases of bacterial infections, especially in lethal cases, has been made, continued cases and outbreaks of these diseases persist, which is caused by different contributing factors. Indeed, during last sixty years antibacterial drugs were used against various infectious diseases caused by bacterial pathogens with an undoubtable success. The most fruitful period for antibiotic development lasted from 40's to 60's of the last century and resulted in the majority of antibiotics currently on the market, which were obtained by screening actinomycetes derived from soil. Although the market for antibacterial drugs is nowadays greater than 25 billion US dollars per year, novel antibacterial drugs are still demanded due to developed resistance of many pathogenic bacteria against current antibiotics. In the last five years, one can observe a dramatic increase in cases of resistant bacteria strains (e.g. Klebsiella pneumoniae and E. coli) which are responsible for difficult to treat pneumonia and infections of urinary tract. The development of resistant bacteria strains is a side effect of antibiotic application for treatment: the infections become untreatable as a result of the existence of antibiotic-tolerant persisters.

In this review, we discuss the challenges in antibacterial drug discovery, including the molecular basis of drug resistance, drug targets for novel antibacterial drugs, and new compounds (since year 2010) from different chemical classes with antibacterial activity, focusing on structure-activity relationships.

Non-Coding RNA in Brain Development and Disorder by Charannya Sozheesvari Subhramanyam, Qidong Hu (1983-1997).
Background: Although up to 90% of the eukaryotic genome can be transcribed, only 1-2% of the resultant transcripts encode for proteins, while the remaining can be classified as non-coding RNAs (ncRNAs) which mostly consist of long ncRNAs (lncRNAs) and small ncRNAs. In overall, they have been suggested to target specific regions in the genome and play multi-faceted roles in many important biological processes.

Summary: Recent evidence has shown that ncRNAs are abundantly expressed in the brain and many of them are aberrantly regulated in neural disorders. Yet their functional relevance in related physiological and pathological processes has not been adequately understood. Thus, the elucidation of the role of ncRNAs in the brain would greatly enhance the current understanding of neural development and ultimately lead to novel strategies to treat neural diseases. In this report, we reviewed the structure and mechanism of lncRNAs and various classes of small ncRNAs in brain development and neural disorders.

Perspective: We hope that extensive studies of these ncRNAs would unravel and characterize novel molecular circuits in the brain, and facilitate the development of RNA-based therapeutics for people suffering from neural disorders.

Chemical and Biological Aspects of the Natural 1,4-Benzoquinone Embelin and its (semi-)Synthetic Derivatives by Priti Singh Shuveksh, Khursheed Ahmed, Subhash Padhye, Rainer Schobert, Bernhard Biersack (1998-2009).
Background: Like the impressive biological properties of embelin, its chemical aspects have raised the interest of scientists in the field as well. A detailed understanding of the chemistry of embelin is necessary to fully exploit it medicinally.

Methods: Search for embelin isolation and its chemical modifications was carried out using web-based literature searching tools such as Pubmed and Scifinder. Pertinent literature is covered up to 2016. Structures of bioactive embelin derivatives are provided.

Results: Pure embelin, obtained from Embelia ribes berries extraction or by total synthesis, was applied for a number of biological assays. Semi-synthetic and total synthetic approaches led to new high affinity embelin-derived inhibitors of crucial protein targets and to new embelin derivatives with improved pharmacological properties (e.g., with better water-solubility or as applications for drug carrier systems).

Conclusion: This review provides a summary of the rich chemistry of embelin and the latest developments in the field of optimized (semi-)synthetic embelin derivatives including their biological activities.