Search

Health-care systems that develop rapidly and efficiently may increase the lifespan of humans. Nevertheless, the older population is more fragile, and is at an increased risk of disease development. A concurrently growing number of surgeries and transplantations have caused antibiotics to be used much more frequently, and for much longer periods of time, which in turn increases microbial resistance. In 1945, Fleming warned against the abuse of antibiotics in his Nobel lecture: "The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant". After 70 years, we are witnessing the fulfilment of Fleming's prophecy, as more than 700,000 people die each year due to drug-resistant diseases. Naturally occurring antimicrobial peptides protect all living matter against bacteria, and now different peptidomimetic strategies to engineer innovative antibiotics are being developed to defend humans against bacterial infections.

The Arg-Gly-Asp (RGD) tripeptide is the smallest recognition sequence for the αvβ3 integrin receptor. A number of nonpeptide analogues of the RGD linear sequence, some of them having improved pharmacological properties, have been proposed in the last two decades. In this study, the stereogenic trifluoroethylamine function was employed as peptide bond surrogate for the development of a new class of RGD peptide mimics. In fact, the trifluoroethylamine group was shown to behave as a peptide-bond surrogate maintaining the H-bond donor capacity of the NH peptide group and a CH(CF3)NH backbone angle close to the native peptide bond 120°. The trifluoroethylamine function is also known to display high metabolic stability and in some cases it positively affects ligand-receptor interactions. Two linear Ψ[CH(CF3)NH]Gly-RGD diastereoisomers were synthesized with good stereocontrol and submitted to biological assays. A remarkable loss in αvβ3 integrin affinity was observed for both compounds, suggesting that the bulky CF3 moiety is not well tolerated within the αvβ3 binding pocket. [ABSTRACT FROM AUTHOR]

• Cell starvation decreases intracellular Tβ4. • Cell starvation increases extracellular peptide uptake. • Cell starvation increases internalization of extracellular Ca2+/Tβ4 complexes. • Internalization of extracellular Ca2+/Tβ4 as an initial signal for cell invasion. Cell metastasis is the main cause of cancer mortality. Inhibiting early events during cell metastasis and invasion could significantly improve cancer prognosis, but the initial mechanisms of cell transition and migration are barely known. Calcium regulates cell migration, whilst Thymosin β4 is a G-actin and iron binding peptide associated with tumor metastasis and ferroptosis. Under normal cell growth conditions, intracellular free calcium ions and Thymosin β4 concentrations are strictly regulated, and are not influenced by extracellular supplementation. However, cell starvation decreases intracellular Thymosin β4 and increases extracellular peptide uptake above the normal range. Unexpectedly, cell starvation significantly increases internalization of extracellular Ca2+/Thymosin β4 complexes. Elucidating the role of Ca2+/Thymosin β4 in the early events of metastasis will likely be important in the future to develop therapies targeting metastasis. [ABSTRACT FROM AUTHOR]