Structural Analysis of Relevant Drug Targets for Alzheimer';s Disease: Novel Approaches to Drug Development

2017 ◽  
Vol 13 (2) ◽  
pp. 90-100 ◽  
Author(s):  
Harolin M. Sosa ◽  
Renee Keyes ◽  
Kimberly A. Stieglitz
Keyword(s):  
Structural Analysis ◽  
Drug Development ◽  
Drug Targets ◽  
Novel Approaches

Current Advances in Clinical Trials for Rare Disease Populations: Spotlight on the Patient

2021 ◽  
Vol 16 ◽  
Author(s):  
Erica Winter ◽  
Scott Schliebner
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Development ◽  
Rare Disease ◽  
Rare Diseases ◽  
Statistical Analyses ◽  
Clinical Trial Designs ◽  
Novel Approaches

: Characterized by small, highly heterogeneous patient populations, rare disease trials magnify the challenges often encountered in traditional clinical trials. In recent years, there have been increased efforts by stakeholders to improve drug development in rare diseases through novel approaches to clinical trial designs and statistical analyses. We highlight and discuss some of the current and emerging approaches aimed at overcoming challenges in rare disease clinical trials, with a focus on the ultimate stakeholder, the patient.

scholarly journals Insights into Ebola Virus VP35 and VP24 Interferon Inhibitory Functions and their Initial Exploitation as Drug Targets

2019 ◽  
Vol 19 (4) ◽  
pp. 362-374 ◽  
Author(s):  
Elisa Fanunza ◽  
Aldo Frau ◽  
Angela Corona ◽  
Enzo Tramontano
Keyword(s):  
Drug Development ◽  
Drug Targets ◽  
Cellular Response ◽  
Ebola Virus ◽  
Virus Disease ◽  
Structural Characteristics ◽  
Inhibitory Function ◽  
The Family ◽  
Effective Shield ◽  
Cellular Immune

Upon viral infection, the interferon (IFN) system triggers potent antiviral mechanisms limiting viral growth and spread. Hence, to sustain their infection, viruses evolved efficient counteracting strategies to evade IFN control. Ebola virus (EBOV), member of the family Filoviridae, is one of the most virulent and deadly pathogen ever faced by humans. The etiological agent of the Ebola Virus Disease (EVD), EBOV can be undoubtedly considered the perfect example of a powerful inhibitor of the host organism immune response activation. Particularly, the efficacious suppression of the IFN cascade contributes to disease progression and severity. Among the EBOVencoded proteins, the Viral Proteins 35 (VP35) and 24 (VP24) are responsible for the EBOV extreme virulence, representing the core of such inhibitory function through which EBOV determines its very effective shield to the cellular immune defenses. VP35 inhibits the activation of the cascade leading to IFN production, while VP24 inhibits the activation of the IFN-stimulated genes. A number of studies demonstrated that both VP35 and VP24 is validated target for drug development. Insights into the structural characteristics of VP35 and VP24 domains revealed crucial pockets exploitable for drug development. Considered the lack of therapy for EVD, restoring the immune activation is a promising approach for drug development. In the present review, we summarize the importance of VP35 and VP24 proteins in counteracting the host IFN cellular response and discuss their potential as druggable viral targets as a promising approach toward attenuation of EBOV virulence.

scholarly journals A universal CAR-NK cell approach for HIV eradication

2021 ◽  
Vol 5 (3) ◽  
pp. 192-194
Author(s):  
Arosh S. Perera Molligoda Arachchige ◽  
Keyword(s):  
Drug Development ◽  
Hiv Infection ◽  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Nk Cell ◽  
Therapeutic Drug ◽  
Effective Solution ◽  
Hiv Eradication ◽  
Novel Approaches ◽  
The Way

<abstract> <p>No therapeutic drug has been able to completely eradicate HIV-infection so far, even after decades of research. A major challenge in HIV drug development is its immense diversity. NK cells are well-known for their anti-viral and anti-tumor functions. Since recently, NK cells have gained interest of researchers as they have paved the way for novel approaches in controlling HIV-infection supported by promising results observed in cancer immunotherapy trials. Here we report an anti-DNP CAR-NK cell approach introduced by Lim et al. capable of recognizing 2,4-dinitrophenyl tagged to anti-gp160 antibodies, which seemingly provides an effective solution to counteract HIV variability.</p> </abstract>

Two novel approaches: Shifting the drug development paradigm

2012 ◽  
Vol 66 (2) ◽  
pp. 179
Author(s):  
Matthew S. Coffee ◽  
Javelyn R. Evans ◽  
David T. Merriman ◽  
Brian M. Roche
Keyword(s):  
Drug Development ◽  
Novel Approaches ◽  
Development Paradigm

scholarly journals Thiol-to-amine cyclization reaction enables screening of large libraries of macrocyclic compounds and the generation of sub-kilodalton ligands

2019 ◽  
Vol 5 (8) ◽  
pp. eaaw2851 ◽  
Author(s):  
S. S. Kale ◽  
M. Bergeron-Brlek ◽  
Y. Wu ◽  
M. G. Kumar ◽  
M. V. Pham ◽  
...  
Keyword(s):  
Drug Development ◽  
Structure Analysis ◽  
Drug Targets ◽  
Macrocyclic Ligands ◽  
Cyclization Reaction ◽  
Thrombin Inhibitor ◽  
Macrocyclic Compounds ◽  
Cyclization Reactions ◽  
X Ray ◽  
High Yields

Macrocyclic compounds are an attractive modality for drug development, but the limited availability of large, structurally diverse macrocyclic libraries hampers the discovery of leads. Here, we describe the discovery of efficient macrocyclization reactions based on thiol-to-amine ligations using bis-electrophiles, their application to synthesize and screen large libraries of macrocyclic compounds, and the identification of potent small macrocyclic ligands. The thiol-to-amine cyclization reactions showed unexpectedly high yields for a wide substrate range, which obviated product purification and enabled the generation and screening of an 8988 macrocycle library with a comparatively small effort. X-ray structure analysis of an identified thrombin inhibitor (Ki = 42 ± 5 nM) revealed a snug fit with the target, validating the strategy of screening large libraries with a high skeletal diversity. The approach provides a route for screening large sub-kilodalton macrocyclic libraries and may be applied to many challenging drug targets.

Structural analysis of malaria-parasite lysyl-tRNA synthetase provides a platform for drug development

2013 ◽  
Vol 69 (5) ◽  
pp. 785-795 ◽  
Author(s):  
Sameena Khan ◽  
Ankur Garg ◽  
Noelia Camacho ◽  
Jason Van Rooyen ◽  
Anil Kumar Pole ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Drug Development ◽  
Malaria Parasite ◽  
Trna Synthetase

scholarly journals FBDD: In-silico STRATEGY TO INHIBIT MPRO ACTIVITY USING DRUGS FROM PREVIOUS OUTBREAKS

2021 ◽  
Vol 9 (4) ◽  
pp. 472-480
Author(s):  
Gauravi N Trivedi ◽  
◽  
Janhavi T Karlekar ◽  
Khushbu Dhimmar ◽  
Hetal kumar Panchal ◽  
...  
Keyword(s):  
Drug Development ◽  
In Silico ◽  
Drug Targets ◽  
Transmission Rate ◽  
Respiratory Illness ◽  
Primary Treatment ◽  
Rational Drug Design ◽  
New Drugs ◽  
Main Protease

Main protease (Mpro) and Spike (S) proteins are said potential drug targets of COVID-19. Pneumonia like respiratory illness caused by SARS-CoV-2 is spreading rapidly due to its replication and transmission rate. Protease is the protein that is involved in both replication and transcription. Since CoV-2 shares, genomic similarity with CoV and MERS-CoV, drugs from previous outbreaks are used as primary treatment of the disease. In-silico drug development strategies are said to be faster and effective than in-vitro with a lesser amount of risk factors. Fragment Based Drug Designing (FBDD), also known as rational drug design in which a potential target protein is selected and docked with a lead-like molecule that eventually leads to drug development. Nine (9) drugs that are currently being used to treat patients of coronavirus were selected in this study from the latest literature review and fragmented as per rules followed by crosslinking of drug fragments using editor tools. These native drugs and synthesized drugs were then docked against the main protease. Results of the study revealed that one of the crosslinked lead-like compounds showed a higher binding affinity (∆G) more than any of the native compounds. Further, the results of this study suggested that the combination of potential drugs can be an effective way to develop new drugs to treat a deadly disease.

scholarly journals Structure-based Druggability Assessment of Anti-virulence Targets from Pseudomonas aeruginosa

2019 ◽  
Vol 20 (12) ◽  
pp. 1189-1203 ◽  
Author(s):  
Thamires Q. Froes ◽  
Regina L. Baldini ◽  
Sandor Vajda ◽  
Marcelo S. Castilho
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Drug Development ◽  
In Silico ◽  
Global Economy ◽  
Drug Targets ◽  
Attractive Alternative ◽  
Antibacterial Drug ◽  
Hotspot Analysis ◽  
Combined Use ◽  
Druggable Targets

Antimicrobial Resistance (AMR) represents a serious threat to health and the global economy. However, interest in antibacterial drug development has decreased substantially in recent decades. Meanwhile, anti-virulence drug development has emerged as an attractive alternative to fight AMR. Although several macromolecular targets have been explored for this goal, their druggability is a vital piece of information that has been overlooked. This review explores this subject by showing how structure- based freely available in silico tools, such as PockDrug and FTMap, might be useful for designing novel inhibitors of the pyocyanin biosynthesis pathway and improving the potency/selectivity of compounds that target the Pseudomonas aeruginosa quorum sensing mechanism. The information provided by hotspot analysis, along with binding site features, reveals novel druggable targets (PhzA and PhzS) that remain largely unexplored. However, it also highlights that in silico druggability prediction tools have several limitations that might be overcome in the near future. Meanwhile, anti-virulence drug targets should be assessed by complementary methods, such as the combined use of FTMap/PockDrug, once the consensus druggability classification reduces the risk of wasting resources on undruggable proteins.

scholarly journals Dethioacylation by Sirtuins 1–3: Considerations for Drug Design using Mechanism-based Sirtuin Inhibition

2020 ◽  
Author(s):  
Nima Rajabi ◽  
Alexander Lund Nielsen ◽  
Christian Adam Olsen
Keyword(s):  
Drug Design ◽  
Drug Development ◽  
Drug Targets ◽  
Short Chain ◽  
Potential Drug ◽  
Serum Stability ◽  
High Affinity ◽  
The Stability ◽  
Potential Drug Targets

The sirtuin enzymes are potential drug targets for intervention in a series of diseases. Efforts to inhibit enzymes of this class with thioamide- and thiourea-containing, substrate-mimicking entities have produced a number of high-affinity binders. However, less attention has been dedicated to the investigation of the stability of these inhibitors under various conditions. Here, we provide evidence of unprecedented degree of cleavage of short-chain epsilon-<i>N</i>-thioacyllysine modifications meant to target these sirtuins and further provide insights into the serum stability of compounds containing both thioamides and thioureas. Our study questions the utility short-chain thioamide-based inhibitors of sirtuins for drug development and points to application of mono-alkylated thiourea-based chemotypes as more promising for targeting sirtuins 1 and 3, in particular.

scholarly journals Defeating Antibiotic-Resistant Bacteria: Exploring Alternative Therapies for a Post-Antibiotic Era

2020 ◽  
Vol 21 (3) ◽  
pp. 1061 ◽  
Author(s):  
Chih-Hung Wang ◽  
Yi-Hsien Hsieh ◽  
Zachary M. Powers ◽  
Cheng-Yen Kao
Keyword(s):  
Drug Targets ◽  
Resistant Bacteria ◽  
Combination Therapies ◽  
Antibiotic Resistant Bacteria ◽  
Antibiotic Resistant ◽  
Alternative Drug ◽  
Novel Approaches ◽  
Antibiotic Discovery ◽  
Medical Advances ◽  
Common Infections

Antibiotics are one of the greatest medical advances of the 20th century, however, they are quickly becoming useless due to antibiotic resistance that has been augmented by poor antibiotic stewardship and a void in novel antibiotic discovery. Few novel classes of antibiotics have been discovered since 1960, and the pipeline of antibiotics under development is limited. We therefore are heading for a post-antibiotic era in which common infections become untreatable and once again deadly. There is thus an emergent need for both novel classes of antibiotics and novel approaches to treatment, including the repurposing of existing drugs or preclinical compounds and expanded implementation of combination therapies. In this review, we highlight to utilize alternative drug targets/therapies such as combinational therapy, anti-regulator, anti-signal transduction, anti-virulence, anti-toxin, engineered bacteriophages, and microbiome, to defeat antibiotic-resistant bacteria.

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