De Novo Design of Lipopeptide-Based β-Sheet-Like Self-Assemblies: A Strategy to Develop Fusion Inhibitors as Broad-Spectrum Antivirals.

The recent surge in emerging viral infections warrants the design of broad-spectrum antivirals. We aim to develop a lead molecule that targets a common biochemical feature of many enveloped viruses, membrane fusion. To achieve the broad-spectrum ability, instead of targeting the fusion machinery, we plan to modulate the physicochemical properties of the host and viral membranes to block fusion.

Phosphate-Based Amphiphile and Lipidated Lysine Assemble into Superior Protocellular Membranes over Carboxylate and Sulfate-Based Systems: A Potential Missing Link between Prebiotic and the Modern Era?

Amphiphiles are among the most extensively studied building blocks that self-assemble into cell-like compartments. Most literature suggested that the building blocks/amphiphiles of early Earth (fatty acid-based membrane) were much simpler than today's phospholipids. To establish the bridge between the prebiotic fatty acid era and the modern phospholipid era, the investigation and characterization of alternate building blocks that form protocellular membranes are necessary.

Heterogeneity and Compositional Diversities of Outer Membrane Vesicles (OMVs) Drive Multiple Cellular Uptake Processes.

Naturally secreted outer membrane vesicles (OMVs) from gut microbes carry diverse cargo, including proteins, nucleic acids, toxins, and many unidentified secretory factors. Bacterial OMVs can shuttle molecules across different cell types as a generalized secretion system, facilitating bacterial pathogenicity and self-survival. Numerous mucosal pathogens, including (), share a mechanism of harmonized secretion of major virulence factors.

Molecular-level insights into a tripolyphosphate and pyrophosphate templated membrane assembly.

Templated assembly of small molecules into nano-structural architectures has been used extensively by nature throughout its evolution. These systems have also been studied in artificial systems to design a phosphate templated assembly. However, it is yet to be investigated how the molecules interact among themselves at the molecular level and whether the phosphate templated assembly has any role in the formation of prebiotic protocellular membranes.

Lipidated Lysine and Fatty Acids Assemble into Protocellular Membranes to Assist Regioselective Peptide Formation: Correlation to the Natural Selection of Lysine over Nonproteinogenic Lower Analogues.

The self-assembly of prebiotically plausible amphiphiles (fatty acids) to form a bilayer membrane for compartmentalization is an important factor during protocellular evolution. Such fatty acid-based membranes assemble at relatively high concentrations, and they lack robust stability. We have demonstrated that a mixture of lipidated lysine (cationic) and prebiotic fatty acids (decanoic acid, anionic) can form protocellular membranes (amino acid-based membranes) at low concentrations via electrostatic, hydrogen bonding, and hydrophobic interactions.

C-Terminal Lipidation of SARS-CoV-2 Fusion Peptide Reinstates Superior Membrane Fusion Catalytic Ability.

The spike (S) protein of severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) mediates a critical stage in infection, the fusion between viral and host membranes. The protein is categorized as a class I viral fusion protein and has two distinct cleavage sites that can be activated by proteases. The activation deploys the fusion peptide (FP) for insertion into the target cell membranes.

Lipid and Lipidation in Membrane Fusion.

Membrane fusion plays a lead role in the transport of vesicles, neurotransmission, mitochondrial dynamics, and viral infection. There are fusion proteins that catalyze and regulate the fusion. Interestingly, various types of fusion proteins are present in nature and they possess diverse mechanisms of action.

Translation of Mycobacterium Survival Strategy to Develop a Lipo-peptide based Fusion Inhibitor*.

The entry of enveloped virus requires the fusion of viral and host cell membranes. An effective fusion inhibitor aiming at impeding such membrane fusion may emerge as a broad-spectrum antiviral agent against a wide range of viral infections. Mycobacterium survives inside the phagosome by inhibiting phagosome-lysosome fusion with the help of a coat protein coronin 1.

A headgroup linker perturbs pKvia acyl chain migration: designing base-labile supramolecular assemblies.

Acyl chain transfer, which perturbs the protonation equilibrium of amine and reduces the apparent pKa by 2.0-2.5 units, is used to develop a liposome-based drug delivery system.