Understanding Lipid Modifications of SARS-CoV-2 Spike Protein
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Chapter 1: Introduction to SARS-CoV-2 Lipid Modifications
The SARS-CoV-2 virus, like many others, relies on its host's biological mechanisms to thrive. This dependence raises intriguing questions about how viruses manipulate host biology. In a recent study conducted by Mesquita et al. from the Global Health Institute at EPFL, Switzerland, it was revealed that lipid modifications play a crucial role in organizing the virus's membrane structures and coordinating the function of its virulence proteins. Notably, the virus lacks its own lipid-modifying enzymes, instead utilizing a host enzyme known as zDHHC, specifically an S-acyltransferase.
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Section 1.1: The Role of the Spike Protein
The research focused on how the Spike protein of SARS-CoV-2 undergoes lipid modifications and which human zDHHC-acetyltransferases are exploited by the virus for this purpose. The investigation was sparked by the observation that the Spike protein contains ten cysteine amino acids within a short loop immediately following its membrane-anchoring domain. Typically, cysteines close to membranes receive lipid attachments, often influencing their functional roles. Here, the membrane pertains to either the virus's own membrane in free infectious particles or the host's membranes during viral assembly. Importantly, the viral membrane consists of lipids derived from the host cells where replication occurs.
The first video illustrates the structure and design of the SARS-CoV-2 spikes, providing valuable insights into its lipid modifications.
Subsection 1.1.1: Mechanism of Infection
SARS-CoV-2's Spike protein is pivotal for its infectivity as it binds to the human ACE2 receptor on target cells, initiating the infection process. The findings of this research indicate that all ten cysteines in the Spike protein are modified through lipid attachments, predominantly by a specific DHHC enzyme that mistakenly recognizes the Spike protein as a natural substrate.
Section 1.2: Impact on Viral Membrane Composition
Our paper also emphasizes that lipid attachment to the Spike protein significantly influences both the lipid composition and organization of the viral membranes. Utilizing molecular dynamics simulations, my contribution demonstrated that lipid modifications to Spike affect its distribution within the membrane and may assist in reshaping the membrane to facilitate the budding of viral capsids from the host cell's membrane. Furthermore, experimental results revealed that viral particles generated in cells lacking the specific zDHHC enzyme exhibited abnormal membrane compositions and a markedly reduced ability to fuse with host cell membranes. In essence, complete lipidation of the Spike protein is essential for the virus's full infectivity.
The second video explores the process of constructing a fully-glycosylated, full-length S protein within a viral membrane, shedding light on the complexities of viral structure.
Chapter 2: Therapeutic Implications and Future Directions
The findings suggest that developing a drug to inhibit the specific zDHHC enzyme's action on the Spike protein could provide a promising avenue for treating viral infections, not just for SARS-CoV-2 but also for other viruses that exploit the host's lipid attachment mechanisms. In our experiments, various chemicals were tested to block lipid addition to the Spike protein, successfully preventing viral infection in cells. While these chemicals are not yet safe for clinical use and do not guarantee an effective treatment, our research has identified a potential target for drug development, marking a critical step in the pursuit of new therapies, often spearheaded by academic laboratories rather than pharmaceutical companies.
Understanding the intricate life cycles of viruses, which are characterized by their ability to hijack host biology, is essential for developing strategies to combat them. Our research has uncovered a new vulnerability in SARS-CoV-2 that could be exploited in future therapeutic efforts. It is my hope that ongoing research in this area will lead to practical applications for human health.
Key Reads
To access the full peer-reviewed article, visit:
For EPFL’s coverage of the study, refer to: