Novel peptide therapeutics against infections caused by enveloped viruses

Emerging viral pathogens, including the pandemic caused by SARS-CoV-2, are rapidly increasing and underscores our limited therapeutic resources against viral infections. Few antiviral drugs exist and they are expensive for widespread use, and treatment of viral infections often includes symptom-reduction by targeting the hosts inflammatory responses.

Viruses are broadly divided into two classes: lipid-enveloped and non-enveloped viruses. Enveloped viruses, such as coronaviridae, herpesviridae, and flaviviridae, use host cells for replication and budding from their membranes. Translation, replication, assembly and budding often occurs in the ER, with following processing in the Golgi apparatus to produce mature viruses, which are then released through exocytosis. The lipid envelope is thus derived from the ER. The lipid composition of the ER membrane differs from that of the plasma membrane, e.g., by an equal distribution of anionic lipids (for example phosphatidylserine) in both leaflets of the ER membrane, while the plasma membrane is assymetric in which all anionic lipids are oriented towards the cytosol. Furthermore, the cholesterol content in the ER membrane is ~8% compared to the plasma membrane that contains ~35%. Amphipathic peptides, including PLNC8 αβ, are interesting candidates against enveloped viruses because of their membrane activity through electrostatic interactions with anionic lipids, which would specifically target extracellular virions without affecting cell viability. This hypothesis has been tested and verified, and is based on data obtained within our group regarding the activity and interactions of PLNC8 αβ. The main objective of this study is to characterize the underlying mechanisms of the antiviral properties of PLNC8 αβ and to develop concepts of drug-delivery. In-depth molecular docking studies are applied in the project, along with molecular dynamics simulations of the interaction between PLNC8 αβ and advanced membrane lipid bilayer models mimicking the viral envelope, plasma membrane, and ER membrane, to study the molecular interactions in detail and to determine peptide diffusion across biological membranes.

Articles

Omer AAM, Hinkula J, Tran P-T-H, Melik W, Zattarin E, Aili D, Selegård R, Bengtsson T, Khalaf H. (2022). Plantaricin NC8 αβ rapidly and efficiently inhibits flaviviruses and SARS-CoV-2 by disrupting their envelopes. PLoS ONE. 17(11):e0278419.