To Discover the Efficient and Novel Drug Targets in Human Cancers Using CRISPR/Cas Screening and Databases

CRISPR/Cas has emerged as an excelle nt gene-editing technology and is used worldwide for research. The CRISPR library is an ideal tool for identifying essential genes and synthetic lethality targeted for cancer therapies in human cancers. Synthetic lethality is defined as multiple genetic abnormalities that, when present individually, do not affect function or survival, but when present together, are lethal. Recently, many CRISPR libraries are available, and the latest libraries are more accurate and can be applied to few cells. However, it is easier to efficiently search for cancer targets with their own screenings by effectively using databases of CRISPR screenings, such as Depmap portal, PICKLES (Pooled In-Vitro CRISPR Knockout Library Essentiality Screens), iCSDB, Project Score database, and CRISP-view. This review will suggest recent optimal CRISPR libraries and effective databases for Novel Approaches in the Discovery and Design of Targeted Therapies.

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Innovative Methodology in the Discovery of Novel Drug Targets in the Free-Living Amoebae

Current Drug Targets ◽

10.2174/1389450119666180426100452 ◽

2018 ◽

Vol 20 (1) ◽

pp. 60-69 ◽

Cited By ~ 3

Author(s):

Abdul Mannan Baig

Keyword(s):

Drug Targets ◽

Mortality Rates ◽

In Vitro Assays ◽

Cancer Drug ◽

Cns Infection ◽

Free Living ◽

Drug Target Discovery ◽

Novel Drug ◽

Novel Drug Targets

Despite advances in drug discovery and modifications in the chemotherapeutic regimens, human infections caused by free-living amoebae (FLA) have high mortality rates (~95%). The FLA that cause fatal human cerebral infections include Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba spp. Novel drug-target discovery remains the only viable option to tackle these central nervous system (CNS) infection in order to lower the mortality rates caused by the FLA. Of these FLA, N. fowleri causes primary amoebic meningoencephalitis (PAM), while the A. castellanii and B. Mandrillaris are known to cause granulomatous amoebic encephalitis (GAE). The infections caused by the FLA have been treated with drugs like Rifampin, Fluconazole, Amphotericin-B and Miltefosine. Miltefosine is an anti-leishmanial agent and an experimental anti-cancer drug. With only rare incidences of success, these drugs have remained unsuccessful to lower the mortality rates of the cerebral infection caused by FLA. Recently, with the help of bioinformatic computational tools and the discovered genomic data of the FLA, discovery of newer drug targets has become possible. These cellular targets are proteins that are either unique to the FLA or shared between the humans and these unicellular eukaryotes. The latter group of proteins has shown to be targets of some FDA approved drugs prescribed in non-infectious diseases. This review out-lines the bioinformatics methodologies that can be used in the discovery of such novel drug-targets, their chronicle by in-vitro assays done in the past and the translational value of such target discoveries in human diseases caused by FLA.

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Novel drug targets for asthma and COPD: Lessons learned from in vitro and in vivo models

Pulmonary Pharmacology & Therapeutics ◽

10.1016/j.pupt.2014.05.008 ◽

2014 ◽

Vol 29 (2) ◽

pp. 181-198 ◽

Cited By ~ 17

Author(s):

Katie E. Baker ◽

Sara J. Bonvini ◽

Chantal Donovan ◽

Rachel E. Foong ◽

Bing Han ◽

...

Keyword(s):

Drug Targets ◽

Lessons Learned ◽

In Vivo Models ◽

Novel Drug ◽

Novel Drug Targets

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Mining the Proteome of Streptococcus mutans for Putative Drug Targets

Infectious Disorders - Drug Targets ◽

10.2174/1871526520666200622143316 ◽

2020 ◽

Vol 20 ◽

Author(s):

Shakti Chandra Vadhana Marimuthu ◽

Haribalaganesh Ravinarayanan ◽

Joseph Christina Rosy ◽

Krishnan Sundar

Keyword(s):

Dental Caries ◽

Streptococcus Mutans ◽

Drug Targets ◽

In Vitro Selection ◽

Target Identification ◽

Dental Enamel ◽

Dental Tissues ◽

Novel Drug ◽

Novel Drug Targets

Background: Dental caries is the most common and one of the prevalent diseases in the world. Streptococcus mutans is one of the major oral pathogen that causes dental caries by forming biofilm on dental tissues, degrading dental enamel and consequent cavitation in the tissue. In vitro selection of drug targets is a laborious and expensive process and therefore computational methods are preferable for target identification at initial stage. Objective: The present research aims to find new drug targets in S. mutans by using subtractive proteomics analysis which implements various bioinformatics tools and databases. Methods: The proteome of S. mutans UA159 was mined for novel drug targets using computational tools and databases such as: CD-HIT, BLASTP, DEG, KAAS and CELL2GO. Results: Out of 1953 proteins of S. mutans UA159, proteins that are non-redundant, non-homologous to human and nonessential to the pathogen were eliminated. Around 178 proteins already available in drug target repositories were also eliminated. Possible functions and subcellular localization of 32 uncharacterized proteins were predicted. Substantially 13 proteins were identified as novel drug targets in S. mutans UA159 that can be targeted by various drugs against dental caries. Conclusion: This study will effectuate the development of novel therapeutic agents against dental carries and other Streptococcal infections.

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Understanding Metabolic Remodeling in Mycobacterium smegmatis to Overcome Energy Exigency and Reductive Stress Under Energy-Compromised State

Frontiers in Microbiology ◽

10.3389/fmicb.2021.722229 ◽

2021 ◽

Vol 12 ◽

Author(s):

Varsha Patil ◽

Vikas Jain

Keyword(s):

Mycobacterium Smegmatis ◽

Energy Efficient ◽

Drug Targets ◽

Redox Homeostasis ◽

Redox Sensor ◽

Metabolic Remodeling ◽

Novel Drug ◽

Novel Drug Targets ◽

Reduced State

Mycobacteria such as Mycobacterium tuberculosis, the causative agent of tuberculosis that annually kills several million people worldwide, and Mycobacterium smegmatis, the non-pathogenic fast-growing mycobacteria, require oxidative phosphorylation to meet their energy requirements. We have previously shown that deletion of one of the two copies of atpD gene that codes for the ATP synthase β-subunit establishes an energy-compromised state in M. smegmatis. Here we report that upon such deletion, a major routing of electron flux occurs through the less energy-efficient complexes of its respiratory chain. ΔatpD bacterium also shows an increased reduced state which is further confirmed by the overexpression of WhiB3, a major redox sensor. We show a substantial modulation of the biosynthesis of cell wall associated lipids and triacylglycerol (TAG). An accumulation of TAG-containing lipid bodies is further confirmed by using 14C oleate incorporation. Interestingly, the mutant also shows an overexpression of TAG-degrading lipase genes, and the intracellular lipolytic enzymes mediate TAG hydrolysis for their utilization as energy source. We believe that our in vitro energy-depleted model will allow us to explore the critical link between energy metabolism, redox homeostasis, and lipid biosynthesis during ATP-depleted state, which will enhance our understanding of the bacterial adaptation, and will allow us to identify novel drug targets to counter mycobacterial infections.

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