Pub Date : 2021-09-09DOI: 10.1021/scimeetings.1c01220
Martha C. Henao, Camila Ocasión, A. Yepes, Juan Burgos Beltrán, Juan C Cruz, Luis H. Reyes
Membranes are natural selective barriers necessary for the correct function of human cells as they control the entry of diverse molecules into the intracellular space Although small and polar molecules such as amino acids and ions cancome across the membrane through channels, larger macromolecules such as proteins and nucleic acids generally failto do so This represents a significant obstacle for efficient intracellular drug delivery, which is essential to increase the bioavailability of pharmacological agents for the treatment of numerous diseases Commonly, diverse methods havebeen studied to mediate the uptake of large molecules, including mechanical and electrical transfection techniques,but also viral carrier systems Some of these methods have been successfully tested in vitro but exhibit biosafety and cytotoxicity issues Inconsequence, there is an increasing interest in the development of novel delivery methods with low cytotoxicity butalso high transduction efficiency An attractive alternative is the cell-penetrating peptides (CPPs), which can beobtained from different origins including signal peptides, viral proteins, or antimicrobial peptides CPPs are generallyshort peptides with lengths between 5-30 amino acids, positively charged or amphipathic, and rich in arginine andlysine Due to their ability to intermingle with the phospholipids of membrane bilayers, some CPPs are able toundergo translocation, and consequently can be considered as promising candidates for the delivery of biologically active molecules to cells The novel coronavirus SARS-CoV-2 has attracted significant attention over the past few months as it is responsible forthe current global sanitary emergency where more than 1 3 M cases have been confirmed and over 70,000 peoplehave died The Spike (S) glycoprotein has been thought to be responsible as the major determinant of the viraltropism towards human cells This protein has a 180 kDa molecular weight and is displayed at the viral surface as atrimer composed of two major domains The first one is the S1, which contains the receptor-binding domain (RBD)responsible for mediating the receptor binding (Angiotensin-converting enzyme 2) The second one is the S2, whichallows the membrane fusion through the exposure of a fusion protein that is activated by proteolytic cleavage in a siteupstream (S2’) and proteolytically primed at the interface of the S1 and S2 domains Transmission of the geneticmaterial into the host cells has been attributed to proteases in priming, receptor binding, and some ionic interactions controlling the stability of the virus By recognizing the strong interaction between de spike (S) glycoprotein of SARS-CoV-2 and the angiotensin-converting enzyme 2 from the cellular membrane of the lung cells, here we aimed at finding motifs that could serve aspossible sources of peptides capable of intermingling with membranes, and eventually with superior translocatingpotency For this purpose, a prediction of the tertiary
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