Current Drug Targets - Volume 23, Issue 3, 2022

Background: Secreted proteases are an important class of factors used by bacterial to modulate their extracellular environment through the cleavage of peptides and proteins. These proteases can range from broad, general proteolytic activity to high degrees of substrate specificity. They are often involved in interactions between bacteria and other species, even across kingdoms, allowing bacteria to survive and compete within their niche. As a result, many bacterial proteases are of clinical importance. The immune system is a common target for these enzymes, and bacteria have evolved ways to use these proteases to alter immune responses for their benefit. In addition to the wide variety of human proteins that can be targeted by bacterial proteases, bacteria also use these secreted factors to disrupt competing microbes, ranging from outright antimicrobial activity to disrupting processes like biofilm formation. Objective: In this review, we address how bacterial proteases modulate host mechanisms of protection from infection and injury, including immune factors and cell barriers. We also discuss the contributions of bacterial proteases to microbe-microbe interactions, including antimicrobial and anti- biofilm dynamics. Conclusion: Bacterial secreted proteases represent an incredibly diverse group of factors that bacteria use to shape and thrive in their microenvironment. Due to the range of activities and targets of these proteases, some have been noted for having potential as therapeutics. The vast array of bacterial proteases and their targets remains an expanding field of research, and this field has many important implications for human health.

Since December 2019, the new Coronavirus disease (COVID-19) caused by the etiological agent SARS-CoV-2 has been responsible for several cases worldwide, becoming pandemic in March 2020. Pharmaceutical companies and academics have joined their efforts to discover new therapies to control the disease since there are no specific drugs to combat this emerging virus. Thus, several tar-gets have been explored; among them, the transmembrane protease serine 2 (TMPRSS2) has gained greater interest in the scientific community. In this context, this review will describe the importance of TMPRSS2 protease and the significant advances in virtual screening focused on discovering new inhibitors. In this review, it was observed that molecular modeling methods could be powerful tools in identifying new molecules against SARS-CoV-2. Thus, this review could be used to guide re-searchers worldwide to explore the biological and clinical potential of compounds that could be promising drug candidates against SARS-CoV-2, acting by inhibition of TMPRSS2 protein.

Antimicrobial Resistance (AMR) is one of the main challenges of today's medicine because it has become a global problem that affects the treatment of multiple infections and impacts public health. This resistance is caused as the bacteria generate selective pressure-promoting mechanisms to evade the action of conventional drugs, which are also associated with adverse effects. Infections caused by these multi-resistant bacteria potentially reduce the possibility of effective therapy; this situation increases morbidity and mortality and treatment costs. Therefore, to establish combined therapy as a strategy for the control of infections caused by multi-resistant bacteria, a bibliographic search was carried out between 2015 and 2020 in databases such as PubMed, Scopus and Science Direct. The exhaustive review of the articles allowed a critical analysis of the information. Mechanisms were identified for obtaining drugs with antimicrobial potential, their biological activity and the possible effect of their combination against multidrug-resistant bacteria as an alternative for infectious disease control and as a response to reduce the use of antibiotics. Combined therapy is presented as an innovative therapeutic alternative, which uses non-antibiotic substances that can be obtained by three routes: the repositioning of drugs, synthetic substances and natural products. In this way, important elements are provided to guide researches that seek to reduce antimicrobial resistance.

Introduction: Alzheimer's disease (AD) is an intensifying neurodegenerative illness due to its irreversible nature. Identification of β128;site Amyloid Precursor Protein (APP) cleaving en-zyme1 (BACE1) has been a significant medicinal focus towards AD treatment, and this has opened ground for several investigations. Despite the numerous works in this direction, no BACE1 inhibitor has made it to the final approval stage as an anti-AD drug. Methods: We provide an introductory background of the subject with a general overview of the pathogenesis of AD. The review features BACE1 inhibitor design and development with a focus on some clinical trials and discontinued drugs. Using the topical keywords BACE1, inhibitor design, and computational/theoretical study in the Web of Science and Scopus database, we retrieved over 49 relevant articles. The search years are from 2010 and 2020, with analysis conducted from May 2020 to March 2021. Results and Discussion: Researchers have employed computational methodologies to unravel po-tential BACE1 inhibitors with a significant outcome. The most used computer-aided approach in BACE1 inhibitor design and binding/interaction studies are pharmacophore development, quantita-tive structure-activity relationship (QSAR), virtual screening, docking, and molecular dynamics (MD) simulations. These methods, plus more advanced ones including quantum mechan-ics/molecular mechanics (QM/MM) and QM, have proven substantial in the computational frame-work for BACE1 inhibitor design. Computational chemists have embraced the incorporation of in vitro assay to provide insight into the inhibition performance of identified molecules with potential inhibition towards BACE1. Significant IC50 values up to 50 nM, better than clinical trial com-pounds, are available in the literature. Conclusion: The continuous failure of potent BACE1 inhibitors at clinical trials is attracting many queries prompting researchers to investigate newer concepts necessary for effective inhibitor de-sign. The considered properties for efficient BACE1 inhibitor design seem enormous and require thorough scrutiny. Lately, researchers noticed that besides appreciable binding affinity and Blood-Brain Barrier (BBB) permeation, BACE1 inhibitor must show low or no affinity for permeability-glycoprotein. Computational modeling methods have profound applications in drug discovery strat-egies. With the volume of recent in silico studies on BACE1 inhibition, the prospect of identifying potent molecules that would reach the approved level is feasible. Investigators should try pushing many of the identified BACE1 compounds with significant anti-AD properties to preclinical and clinical trial stages. We also advise computational research on allosteric inhibitor design, exosite modeling, and multisite inhibition of BACE1. These alternatives might be a solution to BACE1 drug discovery in AD therapy.

Monoamine oxidase (MAO) is an enzyme that catalyzes the deamination of monoamines and other proteins. MAO’s hyperactivation results in the massive generation of reactive oxygen species, which leads to a variety of neurological diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and depression-like disorders. Although synthetic MAO inhibitors are clinically available, they are associated with side effects such as hepatotoxicity, cheese reaction, hypertensive crisis, and so on, necessitating the investigation of alternative MAO inhibitors from a natural source with a safe profile. Herbal medications have a significant impact on the prevention of many diseases; additionally, they have fewer side effects and serve as a precursor for drug development. This review discusses the potential of herbal MAO inhibitors as well as their associated mechanism of action, with an aim to foster future research on herbal MAO inhibitors as a potential treatment for neurological diseases.

Background: In the incretin system, Glucagon-like peptide-1 (GLP-1) is a hormone that inhibits the release of glucagon and regulates glucose-dependent insulin secretion. In type 2 diabetes, correcting the impaired incretin system using GLP-1 agonist is a well-defined therapeutic strategy. Objectives: This review article aims to discuss the mechanism of action, key regulatory events, clinical trials for glycaemic control, and comparative analysis of semaglutide with the second-line antidiabetic drugs. Description: Semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist with enhanced glycaemic control in diabetes patients. In 2019, USFDA approved the first oral GLP-1 receptor agonist, semaglutide, to be administered as a once-daily tablet. Further, recent studies highlight the ability of semaglutide to improve Glycemic control in obese patients with a reduction in body weight. Still, in clinical practice, in the type 2 DM treatment paradigm, the impact of oral semaglutide remains unidentified. This review article discusses the mechanism of action, pharmacodynamics, key regulatory events, and clinical trials regarding glycaemic control. Conclusion: The review highlights the comparative analysis of semaglutide with the existing second- line drugs for the management of type 2 diabetes mellitus by stressing its benefits and adverse events.