Current Drug Targets - Volume 22, Issue 12, 2021

The escalating emergence and prevalence of infections caused by multi-drug resistant (MDR) pathogenic bacteria accentuate the crucial need to develop novel and effectual therapeutic strategies to control this threat. The recent past surprisingly indicates a staggering decline in effective strategies against MDR. Different approaches have been employed to minimize the effect of resistance, but the question still lingers over the astounding number of drugs already tried and tested. Furthermore, the detection of new drug targets and the action of new antibacterial agents against already existing drug targets also complicate the condition. Antibiotic adjuvants are considered as one such promising approach for overcoming bacterial resistance. Adjuvants can potentiate the action of generally adopted antibacterial drugs against MDR bacterial pathogens either by minimizing the impact and emergence of resistance or improving the action of antibacterial drugs. This review provides an overview of the mechanism of antibiotic resistance, the main types of adjuvants and their mode of action, achievements and progression.

Background: Since its initial start in December 2019 at Wuhan, China, the coronavirus disease 2019 (COVID-19) has been rapidly spreading and labelled as a pandemic by the World Health Organization. The rate of human to human transmission of COVID-19 is far higher than severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome coronavirus (MERS). With no drugs or vaccines approved for the treatment of the disease, physicians have been using pre-existing drugs to curb the disease. One potential anti-viral agent currently undergoing numerous clinical trials is remdesivir, a nucleotide analog that inhibits RNA-dependent RNA polymerase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objective: In this mini-review, we provide an overview of remdesivir’s journey, mechanism of action, pharmacokinetics, used in patients with COVID-19 under compassionate use principle and clinical trials to understand the effect of remdesivir in the treatment of patients with COVID-19. Conclusion: Initially, remdesivir was granted an emergency use authorization (EUA) by the U.S. Food and Drug Administration for the treatment of COVID-19 with severe disease. But now, remdesivir has been granted for use under EUA to treat all hospitalized COVID-19 patients, irrespective of their severity of disease.

Background: Conventional medicines, along with herbal formulations of Chinese, serve as the primary source and hub of active new drugs where the initial research concentrates on the extraction and isolation of bioactive lead compound(s) to treat several diseases largely for cancer. Plant-derived natural products and their analogs reveal a significant source of several clinically useful anticancer agents. Herbs and herbal derived active compounds play an unavoidable role in the treatment, drug discovery and delivery for decades, as evidenced by numerous existing marked drugs and various cancer-related molecular targets in clinical development. Objective: Solubility, resistance and metabolic limitations of the drug can be overcome by suitable molecular modifications. Due to enhancements in tumor targeting technology, some agents who failed in earlier clinical studies are also stimulating renewed interest. In this connection, In Vitro-In Vivo Correlation (IVIVC) plays an important role in the development of dosage forms in the field of pharmaceutical technology. Conclusion: IVIVC tool fastens and improves the drug development process and product quality, which is also utilized in internal control for scale-up to improve formulations and alternative production processes. Most importantly, this IVIVC tool lessens the number of human studies during new pharmaceuticals developments. In this review, we would like to grab the attention of readers to the importance and significance of IVIVC for natural products of anticancer drugs examples such as Docetaxel, Etoposide phosphate, 6-Gingerol, Capsaicin, etc.

In neurodegenerative disorders, there is a progressive degeneration of the body, leading to the death of nerve cells. In this state, a patient gets affected day by day with mental weakness, dementia, and ataxia. Alzheimer’s disease (AD) is the most common irreversible neurodegenerative brain disorder mainly affecting people over the age of 65. Many types of research suggest that the main culprit for AD is the aggregated form of a (39-43) amino acid peptide called amyloid beta. Amyloid beta (Aβ) is generated by the action of beta-secretase and gamma-secretase on the larger glycoprotein. Gamma (γ) secretase is an intra-membrane protease complex that cleaves the single-- pass transmembrane protein, the amyloid precursor protein, and Notch. The γ-secretase complex contains presenilin, presenilin enhancer-2, anterior pharynx defective-1, and nicastrin. Any mutation in presenilin-1 or the cleavage of amyloid precursor protein by γ-secretase directly or indirectly is associated with AD. Therefore, the prevention of this enzyme is one of the solutions for AD. In this article, we discuss the γ-secretase complex and its inhibitors that can contribute to the prevention of AD.

One of the most common forms of neurodegenerative disorders, Alzheimer’s disease poses a great threat to patients all over the globe with about 5.7 million cases estimated by the Alzheimer’s Association Report of 2018. The disorder is a result of β-amyloid deposition in the brain, deteriorating the cognitive ability and learning processes, commonly in geriatric patients. The review significantly elaborates the superiority of nanotechnological formulations over conventional therapeutic strategies, which exhibit numerous side effects, poor pharmacokinetic profiles and limited efficacy, as compared to the nano-medicinal approach. The review recognizes the need to establish an understanding of the transport mechanisms across the blood-brain barrier, prior to the nanoparticle studies, followed by a discussion on various nano-formulations, evidently supported by the outcome of various studies conducted to investigate the drug delivery portfolio of nanomedicines. Furthermore, the review portrays the challenges to overcome in future studies, like nanoparticle fabrication, drug loading capacity, blood residency time, toxicity regime, monitoring long term effects, in-vivo compatibility and production techniques, in order to enable the development of an optimized form of drug delivery process, which would achieve significant heights in the biomedical applications and bring about a revolution in the field of medicine and science.

The major health-care burden for the developing world are infectious diseases where antimicrobial agents prove to be the magical drugs to combat this. But the phenomenon of antimicrobial resistance (AMR) represents a challenging global issue, which requires to be addressed effectively. The antimicrobial treatment for the emerging multidrug-resistant bacterial (e.g. TB, Cholera) and fungal (e.g. Candidiasis) infections is very limited, and there are multiple causes and reasons responsible for the evolution of such resistance. Considering the critical issues of increasing AMR, there is an urgent requirement of the identification, development, validation, and progression of novel strategies and approaches that can easily be utilized for overcoming this serious issue. Immunotherapy represents a significant way to improve host defenses and combat the issue of antimicrobial drug resistance. Similarly, drug combination therapy represents another promising approach for reducing the evolution of resistance and enhancing the longevity of the antimicrobial agents. Bacteriophage therapy also acts as a novel therapeutic option to control the development of the multidrug resistance (MDR) phenomenon. Besides, CRISPR, an innovative genome editing technology, offers multiple applications to safeguard host defenses to overcome different resistance challenges. The novel approaches/ strategies like combination therapy, bacteriophage therapy, immunotherapy, and CRISPR/Cas discussed here presents an overview of some of the novel strategies/approaches to be adopted against the pathogenic microbes/microbial invasions along with advanced knowledge of different drug resistance mechanisms adopted by the microbial pathogens to gain resistance against different antimicrobial agents. Therefore, understanding the novel control plans/approaches and different drug resistance mechanisms will help achieve the goals of the successful development of potential antimicrobial drugs and their respective targets and eventually help curtail the problem of increasing antimicrobial drug resistance menace in various human pathogenic microbes.

Background: Glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase enzyme that controls neuronal functions such as neurite outgrowth, synapse formation, neurotransmission, and neurogenesis. The enzyme has two subunits as GSK-3α and GSK-3β. 4ACC, 1Q3D, 3AFG, 1UV5, and 1Q5K are the important GSK-3 receptors isolated from Homo sapiens and Mus musculus. This enzyme mainly phosphorylates Tau protein with the increased amount in neuronal fibres together with beta-amyloid plaques that cause neuronal diseases like Alzheimer's, Parkinson’s and many more. Objective: We investigated the developments of various synthetic GSK-3 inhibitors responsible for the prevention and treatment of neurological disorders, like Alzheimer's disease, bipolar disorders, acting as antidepressants, neuroprotective, etc. Results and Conclusion: It has been observed that structures of the GSK-3 inhibitors are comprised of benzopyridine, benzothiazole, pyrazole, pyrazine, dioxolo-benzoxazine, oxadiazole, and benzimidazole in the skeletal with cyclopropyl amide, phenyl carbamothioate, 3-[(propan- 2-yl)oxy]propan-1-amine in the side chain. The molecules were evaluated against the effectivity of GSK-3, human adenosine kinase, cyclin-dependent kinase, and phosphodiesterase-4 along with tail suspension test forced swim test, percent neuronal survival and other cognitive behaviours. The observations confirmed the remarkable effects of the synthesized molecules to conquer Alzheimer, Parkinson’s depression, psychosis and other forms of neurological disorders.