Optimizing PEG-Extended Apelin Analogues as Cardioprotective Drug Leads: Importance of the KFRR Motif and Aromatic Head Group for Improved Physiological Activity

2020 ◽  
Vol 63 (20) ◽  
pp. 12073-12082 ◽  
Author(s):  
Conrad Fischer ◽  
Tess Lamer ◽  
Kleinberg Fernandez ◽  
Mahmoud Gheblawi ◽  
Wang Wang ◽  
...  
eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Christopher Chidley ◽  
Sunia A Trauger ◽  
Kıvanç Birsoy ◽  
Erin K O'Shea

Phenotypic screens allow the identification of small molecules with promising anticancer activity, but the difficulty in characterizing the mechanism of action of these compounds in human cells often undermines their value as drug leads. Here, we used a loss-of-function genetic screen in human haploid KBM7 cells to discover the mechanism of action of the anticancer natural product ophiobolin A (OPA). We found that genetic inactivation of de novo synthesis of phosphatidylethanolamine (PE) mitigates OPA cytotoxicity by reducing cellular PE levels. OPA reacts with the ethanolamine head group of PE in human cells to form pyrrole-containing covalent cytotoxic adducts and these adducts lead to lipid bilayer destabilization. Our characterization of this unusual cytotoxicity mechanism, made possible by unbiased genetic screening in human cells, suggests that the selective antitumor activity displayed by OPA may be due to altered membrane PE levels in cancer cells.


Author(s):  
Awtar Krishan

Earle's L-929 fibroblasts treated with mitosis-arresting but sub-lethal doses of vinblastine sulfate (VLB) show hypertrophy of the granular endoplasmic reticulum and annulate lamellae. Exposure of the cells to heavier doses of vincristine sulfate (VCR), a VLB-related drug, leads to the accumulation of large amounts of helical polyribosomes, Golgi membranes and crystals in the cytoplasm. In many of these cells a large number of helical polyribosomes are arranged in prominent linear rows, some of which may be up to 5 micrometers in length. Figure 1 shows a large array of helical polyribosomes near a crystalline mass (CRS) in an Earle's L-929 fibroblast exposed to VCR (5ϒ/ml.) for 3 hours At a higher magnification, as seen in figure 2, the helical polyribosomes are seen arranged in parallel rows. In favorably cut sections, a prominent backbone like "stalk" of finely granular material, measuring approximately 300Å in width is seen in close association with the linear rows of helical polyribosomes.


Author(s):  
H. D. Geissinge ◽  
L.D. Rhodes

A recently discovered mouse model (‘mdx’) for muscular dystrophy in man may be of considerable interest, since the disease in ‘mdx’ mice is inherited by the same mode of inheritance (X-linked) as the human Duchenne (DMD) muscular dystrophy. Unlike DMD, which results in a situation in which the continual muscle destruction cannot keep up with abortive regenerative attempts of the musculature, and the sufferers of the disease die early, the disease in ‘mdx’ mice appears to be transient, and the mice do not die as a result of it. In fact, it has been reported that the severely damaged Tibialis anterior (TA) muscles of ‘mdx’ mice seem to display exceptionally good regenerative powers at 4-6 weeks, so much so, that these muscles are able to regenerate spontaneously up to their previous levels of physiological activity.


Planta Medica ◽  
2012 ◽  
Vol 78 (05) ◽  
Author(s):  
SK Jain ◽  
R Sahu ◽  
J Zhang ◽  
MR Jacob ◽  
XC Li ◽  
...  

Planta Medica ◽  
2016 ◽  
Vol 81 (S 01) ◽  
pp. S1-S381
Author(s):  
NT Nyberg ◽  
SG Wubshet ◽  
KT Kongstad ◽  
D Staerk

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