Current Drug Targets - Volume 21, Issue 2, 2020

Ribonucleic acid (RNA) viruses associated with chronic diseases in humans are major threats to public health causing high mortality globally. The high mutation rate of RNA viruses helps them to escape the immune response and also is responsible for the development of drug resistance. Chronic infections caused by human immunodeficiency virus (HIV) and hepatitis viruses (HBV and HCV) lead to acquired immunodeficiency syndrome (AIDS) and hepatocellular carcinoma respectively, which are one of the major causes of human deaths. Effective preventative measures to limit chronic and re-emerging viral infections are absolutely necessary. Each class of antiviral agents targets a specific stage in the viral life cycle and inhibits them from its development and proliferation. Most often, antiviral drugs target a specific viral protein, therefore only a few broad-spectrum drugs are available. This review will be focused on the selected viral target proteins of pathogenic viruses containing single-stranded (ss) RNA genome that causes chronic infections in humans (e.g. HIV, HCV, Flaviviruses). In the recent past, an exponential increase in the number of available three-dimensional protein structures (>150000 in Protein Data Bank), allowed us to better understand the molecular mechanism of action of protein targets and antivirals. Advancements in the in silico approaches paved the way to design and develop several novels, highly specific small-molecule inhibitors targeting the viral proteins.

Homeostasis in the cardiovascular system is maintained by physiological functions of the Renin Angiotensin Aldosterone System (RAAS). In pathophysiological conditions, over activation of RAAS leads to an increase in the concentration of Angiotensin II (AngII) and over activation of Angiotensin Type 1 Receptor (AT1R), resulting in vasoconstriction, sodium retention and change in myocyte growth. It causes cardiac remodeling in the heart which results in left ventricular hypertrophy, dilation and dysfunction, eventually leading to Heart Failure (HF). Inhibition of RAAS using angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) has shown to significantly reduce morbidity and mortality due to HF. ACEi have been shown to have higher drug withdrawal rates due to discomfort when compared to ARBs; therefore, ARBs are the preferred choice of physicians for the treatment of HF in combination with other anti-hypertensive agents. Currently, eight ARBs have been approved by FDA and are clinically used. Even though they bind to the same site of AT1R displacing AngII binding but clinical outcomes are significantly different. In this review, we described the clinical significance of each ARB in the treatment of HF and their clinical outcome.

Ion channels are integral proteins expressed in almost all living cells and are involved in muscle contraction and nutrient transport. They play a critical role in the normal functioning of the excitable tissues of the nervous system and regulate the action potential and contraction events. Dysfunction of genes encodes ion channel proteins, which disrupt the channel function and lead to a number of diseases, among which is type 1 diabetes mellitus (T1DM). Therefore, understanding the complex mechanism of ion channel receptors is necessary to facilitate the diagnosis and management of treatment. In this review, we summarize the mechanism of important ion channels and their potential role in the regulation of insulin secretion along with the limitations of ion channels as therapeutic targets. Furthermore, we discuss the recent investigations of the mechanism regulating the ion channels in pancreatic beta cells, which suggest that ion channels are active participants in the regulation of insulin secretion.

Alzheimer’s disease (AD) is one of the most common forms of dementia and has been a global concern for several years. Due to the multi-factorial nature of the disease, AD has become irreversible, fatal and imposes a tremendous socio-economic burden. Even though experimental medicines suggested moderate benefits, AD still lacks an effective treatment strategy for the management of symptoms or cure. Among the various hypotheses that describe development and progression of AD, the amyloid hypothesis has been a long-term adherent to the AD due to the involvement of various forms of Amyloid beta (Aβ) peptides in the impairment of neuronal and cognitive functions. Hence, majority of the drug discovery approaches in the past have focused on the prevention of the accumulation of Aβ peptides. Currently, there are several agents in the phase III clinical trials that target Aβ or the various macromolecules triggering Aβ deposition. In this review, we present the state of the art knowledge on the functional aspects of the key players involved in the amyloid hypothesis. Furthermore, we also discuss anti-amyloid agents present in the Phase III clinical trials.

The standard treatment for advanced ovarian cancer is cytoreductive surgery followed by cytotoxic chemotherapy. However, it has high risk of recurrence and poor prognosis. Poly(ADPribose) polymerase (PARP) inhibitors selectively target DNA double-strand breaks (DSBs) in tumor cells that cannot be repaired and induce the synthetic lethality of BRCA1/2 mutation cancers. PARP inhibitors are clinically used to treat recurrent ovarian cancer and show significant efficacy in ovarian cancer patients with homologous recombination repair (HRR) pathway defects. PARP inhibitors also have significant clinical benefits in patients without HR defects. With the increasingly extensive clinical application of PARP inhibitors, the possibility of acquiring drug resistance is high. Therefore, clinical strategies should be adopted to manage drug resistance of PARP inhibitors. This study aims to summarize the indications and toxicity of PARP inhibitors, the mechanism of action, targeted treatment of drug resistance, and potential methods to manage drug-resistant diseases. We used the term “ovarian cancer” and the names of each PARP inhibitor as keywords to search articles published in the Medical Subject Headings (MeSH) on Pubmed, along with the keywords “clinicaltrials.gov” and “google.com/patents” as well as “uspto.gov.” The FDA has approved olaparib, niraparib, and rucaparib for the treatment of recurrent epithelial ovarian cancer (EOC). Talazoparib and veliparib are currently in early trials and show promising clinical results. The mechanism underlying resistance to PARP inhibitors and the clinical strategies to overcome them remain unclear. Understanding the mechanism of resistance to PARP inhibitors and their relationship with platinum resistance may help with the development of antiresistance therapies and optimization of the sequence of drug application in the future clinical treatment of ovarian cancer.

Background: The lipid bilayer of the plasma membrane is impermeable to ions, yet changes in the flux of ions across the cell membrane are critical regulatory events in cells. Because of their regulatory roles in a range of physiological processes, such as electrical signaling in muscles and neurons, to name a few, these proteins are one of the most important drug targets. Objective: This review mainly focused on the computational approaches for elucidating proteinprotein interactions in cation channel signaling. Discussion: Due to continuously advanced facilities and technologies in computer sciences, the physical contacts of macromolecules of channel structures have been virtually visualized. Indeed, techniques like protein-protein docking, homology modeling, and molecular dynamics simulation are valuable tools for predicting the protein complex and refining channels with unreleased structures. Undoubtedly, these approaches will greatly expand the cation channel signaling research, thereby speeding up structure-based drug design and discovery. Conclusion: We introduced a series of valuable computational tools for elucidating protein-protein interactions in cation channel signaling, including molecular graphics, protein-protein docking, homology modeling, and molecular dynamics simulation.

A hallmark feature of severe Group A Streptococcus pyogenes (GAS) infection is dysregulated hemostasis. Hemostasis is the primary pathway for regulating blood flow through events that contribute towards clot formation and its dissolution. However, a number of studies have identified components of hemostasis in regulating survival and dissemination of GAS. Several proteins have been identified on the surface of GAS and they serve to either facilitate invasion to host distal sites or regulate inflammatory responses to the pathogen. GAS M-protein, a surface-exposed virulence factor, appears to be a major target for interactions with host hemostasis proteins. These interactions mediate biochemical events both on the surface of GAS and in the solution when M-protein is released into the surrounding environment through shedding or regulated proteolytic processes that dictate the fate of this pathogen. A thorough understanding of the mechanisms associated with these interactions could lead to novel approaches for altering the course of GAS pathogenicity.

Background: Influenza is a single-stranded RNA virus that is highly contagious and infects millions of people in the U.S. annually. Due to complications, approximately 959,000 people were hospitalized and another 79,400 people died during the 2017-2018 flu season. While the best methods of prevention continue to be vaccination and hygiene, antiviral treatments may help reduce symptoms for those who are infected. Until recently, the only antiviral drugs in use have been the neuraminidase inhibitors: oseltamivir, zanamivir, and peramivir. Objective: We reviewed novel drug targets that can be used in the treatment of influenza, particularly in the case of neuraminidase inhibitor-resistant strains that may emerge. Results: More recently, a drug with a new mechanism of action has been approved. Baloxavir marboxil inhibits the influenza cap-dependent endonuclease that is needed for the virus to initiate replication within the host cell. This endonuclease target is within the polymerase acid (PA) subunit of RNA polymerase. Since the RNA-dependent RNA polymerase consists of two other subunits, polymerase basic 1 and 2, RNA polymerase has several targets that prevent viral replication. Other targets still under investigation include viral kinases, endocytosis, and viral fusion. Conclusion: Due to the possibility of viral mutations and resistance, it is important to have antivirals with different mechanisms available, especially in the case of a new pandemic strain. Several novel antivirals are within various stages of development and may represent new classes of treatments that can reduce symptoms and complications in those patients who may be at higher risk.