Search results for "Drug development"

Discovery and validation of small-molecule heat-shock protein 90 inhibitors through multimodality molecular imaging in living subjects.

2012

Up-regulation of the folding machinery of the heat-shock protein 90 (Hsp90) chaperone protein is crucial for cancer progression. The two Hsp90 isoforms (α and β) play different roles in response to chemotherapy. To identify isoform-selective inhibitors of Hsp90(α/β)/cochaperone p23 interactions, we developed a dual-luciferase (Renilla and Firefly) reporter system for high-throughput screening (HTS) and monitoring the efficacy of Hsp90 inhibitors in cell culture and live mice. HTS of a 30,176 small-molecule chemical library in cell culture identified a compound, N -(5-methylisoxazol-3-yl)-2-[4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-ylthio]acetamide (CP9), that binds to Hsp90(α/β) an…

Development of Novel Benzodiazepine-Based Peptidomimetics as Inhibitors of Rhodesain from Trypanosoma brucei rhodesiense.

2020

Starting from the reversible rhodesain inhibitors 1 a-c, which have Ki values towards the target protease in the low-micromolar range, we have designed a series of peptidomimetics, 2 a-g, that contain a benzodiazepine scaffold as a β-turn mimetic; they are characterized by a specific peptide sequence for the inhibition of rhodesain. Considering that irreversible inhibition is strongly desirable in the case of a parasitic target, a vinyl ester moiety acting as Michael-acceptor was introduced as the warhead; this portion was functionalized in order to evaluate the size of corresponding enzyme pocket that could accommodate this substituent. With this investigation, we identified an irreversibl…

Sortase A: An ideal target for anti-virulence drug development

2014

Sortase A is a membrane enzyme responsible for the anchoring of surface-exposed proteins to the cell wall envelope of Gram-positive bacteria. As a well-studied member of the sortase subfamily catalysing the cell wall anchoring of important virulence factors to the surface of staphylococci, enterococci and streptococci, sortase A plays a critical role in Gram-positive bacterial pathogenesis. It is thus considered a promising target for the development of new anti-infective drugs that aim to interfere with important Gram-positive virulence mechanisms, such as adhesion to host tissues, evasion of host defences, and bio fi lm formation. The additional properties of sortase A as an enzyme that i…

“Role of biomarkers in the regulatory process”

2007

Potential of ‘Omics’ Technologies for Implementation in Research on Phytotherapeutical Toxicology

2012

Abstract High toxicity is the most common reason why new agents drop out of drug development in the pharmaceutical industry. There is hope that toxicogenomics facilitates the early detection of toxic effects and their molecular mechanisms of action during preclinical studies to remove potentially toxic substances from the development. Herbal remedies consist of mixtures of different herbs, which represent a considerable source of heterogeneity and toxicity. They may be caused by botanical misidentification, contamination with pesticides, heavy metals, organic solvents, microbials and radioactivity. Intentional faked herbal products may contain chemical drugs or hormones. Approaches to apply…

<strong>Artemisinin: Tentative Mechanism of Action and Resistance</strong>

2016

The sesquiterpene lactones constitute a large class of secondary plant metabolites, which carry a‑methylene‑g‑lactone groups as common structural element and display a number of bioactivities. Every year, 1–2 million people living in the tropics and subtropics die of malaria. Lactone artemisinin is the most effective treatment vs. malaria, the most infectious disease in the world today. Artemisinins are derived from extracts of sweet wormwood (Artemisia annua) and are well established for the treatment of malaria, e.g., highly drug-resistant strains. They resulted in one of the most significant advances in the treatment of malaria since the discovery and first use of quinine over 300 years …

Development and biological investigations of hypoxia-sensitive prodrugs of the tyrosine kinase inhibitor crizotinib

2019

Despite the huge success of tyrosine kinase inhibitors as anticancer agents, severe side effects are a major problem. In order to overcome this drawback, the first hypoxia-activatable 2-nitroimidazole-based prodrugs of the clinically approved ALK and c-MET inhibitor crizotinib were developed. The 2-aminopyridine functionality of crizotinib (essential for target kinase binding) was considered as ideal position for prodrug derivatization. Consequently, two different prodrugs were synthesized with the nitroimidazole unit attached to crizotinib either via carbamoylation (A) or alkylation (B) of the 2-aminopyridine moiety. The successful prodrug design could be proven by docking studies and a dr…

Inclusion of pregnant women in clinical trials of COVID-19 therapies: what have we learned?

2020

PHP7 Orphan Drugs for Rare Diseases in the European Union: Bridging the Gap between Drug Development and Unmet Medical Needs?

2011

Will it ever become possible to prevent dopaminergic neuronal degeneration?

2008

Parkinsons disease (PD) is the second leading age-related degenerative brain disease in the world affecting millions of people. This neurological disorder disrupts the quality of life of patients and their families, exerts an enormous emotional and physical strain on caregivers, and has a large cost for society. Moreover, the increasing numbers of elderly people in the population will result in a sharp increase in the prevalence of PD. The understanding of its pathophysiology and treatment has advanced at a very impressive rate during past decades. Nevertheless, PD is still fatal and there is at present no cure for it. Furthermore, there are no proven therapies for prevention of PD and alth…