(296d) Study of the Spike (S) Glycoprotein from the Sars-Cov-2 As a Possible Source of Translocating Peptides of Biomedical Interest
AIChE Annual Meeting
Monday, November 16, 2020 - 8:45am to 9:00am
Some of these methods have been successfully tested in vitro but exhibit biosafety and cytotoxicity issues3. In consequence, there is an increasing interest in the development of novel delivery methods with low cytotoxicity but also high transduction efficiency1. An attractive alternative is the cell-penetrating peptides (CPPs), which can be obtained from different origins including signal peptides, viral proteins, or antimicrobial peptides4. CPPs are generally short peptides with lengths between 5-30 amino acids, positively charged or amphipathic, and rich in arginine and lysine3. Due to their ability to intermingle with the phospholipids of membrane bilayers, some CPPs are able to undergo 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 for the current global sanitary emergency where more than 1.3 M cases have been confirmed and over 70,000 people have died5. The Spike (S) glycoprotein has been thought to be responsible as the major determinant of the viral tropism towards human cells6. This protein has a 180 kDa molecular weight and is displayed at the viral surface as a trimer composed of two major domains7. 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, which allows the membrane fusion through the exposure of a fusion protein that is activated by proteolytic cleavage in a site upstream (S2â) and proteolytically primed at the interface of the S1 and S2 domains. Transmission of the genetic material into the host cells has been attributed to proteases in priming, receptor binding, and some ionic interactions controlling the stability of the virus7.
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 as possible sources of peptides capable of intermingling with membranes, and eventually with superior translocating potency. For this purpose, a prediction of the tertiary structure of the S protein from the SARS-CoV-2 was performed by homology, using Phyre Server, with the S protein from the bat coronavirus RaTG13. This was selected due to its closeness to the SARS-CoV-2 virus as it shares more than 93% of the identity in the S gene8. Simultaneously, the structure was also predicted de novo using the iTASSER Server to assure that predictions were robust enough for biophysical interaction studies. To determine the motifs with significant membrane activity (and potential translocation ability), a prediction of the possible formed transmembrane helices was carried out using TMHMM Server v. 2.0. Finally, the selected sequences were studied into detail via molecular dynamics (MD), using a mode membrane.
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