Lipid Membrane Interface Viewpoint: From Viral Entry to Antiviral and Vaccine Development

Abstract

Membrane-enveloped viruses are responsible for most viral pandemics in history, and more effort is needed to advance broadly applicable countermeasures to mitigate the impact of future outbreaks. In this Perspective, we discuss how biosensing techniques associated with lipid model membrane platforms are contributing to improving our mechanistic knowledge of membrane fusion and destabilization that is closely linked to viral entry as well as vaccine and antiviral drug development. A key benefit of these platforms is the simplicity of interpreting the results which can be complemented by other techniques to decipher more complicated biological observations and evaluate the biophysical functionalities that can be correlated to biological activities. Then, we introduce exciting application examples of membrane-targeting antivirals that have been refined over time and will continue to improve based on biophysical insights. Two ways to abrogate the function of viral membranes are introduced here: (1) selective disruption of the viral membrane structure and (2) alteration of the membrane component. While both methods are suitable for broadly useful antivirals, the latter also has the potential to produce an inactivated vaccine. Collectively, we emphasize how biosensing tools based on membrane interfacial science can provide valuable information that could be translated into biomedicines and improve their selectivity and performance.

Alkyl Derivatives of Perylene Photosensitizing Antivirals: Towards Understanding the Influence of Lipophilicity

“…In order to investigate the behavior of perylene derivatives 12 and 14 with alkyl chains of different lengths-C 0 (12,14), C 4 (12a,14a), C 8 (12b,14b), and C 12 (12c,14c)-in a lipid bilayer, we performed a set of molecular dynamics (MD) simulations. In MD trajectories, the initially water-exposed perylene derivatives are rapidly (within 20-50 ns) inserted into the lipid bilayer, regardless of alkyl tail length.…”

“…The lipid membrane fusion occurs via pre-fusion → hemifusion → pore formation steps, initiating the infection process (Figure 1). Consequently, targeting viral membrane fusion has emerged as a promising strategy in the development of potent antiviral agents [9][10][11][12][13][14][15]. Virions lack molecular repair systems, so damage to their envelope by a direct-acting antiviral can inhibit fusion.…”

“…Antiviral activity of synthesized (lipophilized) compounds (9-15a-c) and their analogs without lipophilization(9)(10)(11)(12)(13)(14)(15). Results are shown as EC 50 in µM.…”

Antiviral activity of singlet oxygen-photogenerating perylene compounds against SARS-CoV-2: Interaction with the viral envelope and photodynamic virion inactivation

“…Since membranes are a highly evolutionarily conserved structural element for all enveloped viruses, and because membranes are not linked to the viral genomes through the replication-transcription-translation machinery, RAFIs have the potential to be broad-spectrum antiviral agents with an extremely high resistance barrier ( St.Vincent et al., 2010 ). Targeting the viral lipid membrane is an important recent trend in the development of antivirals and vaccines ( Correa Sierra and Schang, 2022 ; Park and Cho, 2023 ; Sardar et al., 2022 ). Although both suggested mechanisms involve the inhibition of virion-cell fusion, the name RAFI emphasizes the molecule's geometric shape and polarity, not the presence of a photosensitizing chromophore.…”