- Bio21 - Research Publications
Bio21 - Research Publications
Permanent URI for this collection
3 results
Filters
Reset filtersSettings
Statistics
Citations
Search Results
Now showing
1 - 3 of 3
-
ItemNo Preview AvailablePharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failureFaysal, KMR ; Walsh, JC ; Renner, N ; Marquez, CL ; Shah, VB ; Tuckwell, AJ ; Christie, MP ; Parker, MW ; Turville, SG ; Towers, GJ ; James, LC ; Jacques, DA ; Bocking, T (eLIFE SCIENCES PUBL LTD, 2024-02-13)The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved for medical use. Here, we investigate the effect of lenacapavir on HIV capsid stability and uncoating. We employ a single particle approach that simultaneously measures capsid content release and lattice persistence. We demonstrate that lenacapavir's potent antiviral activity is predominantly due to lethal hyperstabilisation of the capsid lattice and resultant loss of compartmentalisation. This study highlights that disrupting capsid metastability is a powerful strategy for the development of novel antivirals.
-
ItemNo Preview AvailableCholesterol-dependent cytolysins: The outstanding questionsJohnstone, BA ; Joseph, R ; Christie, MP ; Morton, CJ ; McGuiness, C ; Walsh, JC ; Bocking, T ; Tweten, RK ; Parker, MW (WILEY, 2022-12)The cholesterol-dependent cytolysins (CDCs) are a major family of bacterial pore-forming proteins secreted as virulence factors by Gram-positive bacterial species. CDCs are produced as soluble, monomeric proteins that bind specifically to cholesterol-rich membranes, where they oligomerize into ring-shaped pores of more than 30 monomers. Understanding the details of the steps the toxin undergoes in converting from monomer to a membrane-spanning pore is a continuing challenge. In this review we summarize what we know about CDCs and highlight the remaining outstanding questions that require answers to obtain a complete picture of how these toxins kill cells.
-
ItemSingle-molecule analysis of the entire perfringolysin O pore formation pathwayMc Guinness, C ; Walsh, JC ; Bayly-Jones, C ; Dunstone, MA ; Christie, MP ; Morton, CJ ; Parker, MW ; Bocking, T (eLIFE SCIENCES PUBL LTD, 2022-08-24)The cholesterol-dependent cytolysin perfringolysin O (PFO) is secreted by Clostridium perfringens as a bacterial virulence factor able to form giant ring-shaped pores that perforate and ultimately lyse mammalian cell membranes. To resolve the kinetics of all steps in the assembly pathway, we have used single-molecule fluorescence imaging to follow the dynamics of PFO on dye-loaded liposomes that lead to opening of a pore and release of the encapsulated dye. Formation of a long-lived membrane-bound PFO dimer nucleates the growth of an irreversible oligomer. The growing oligomer can insert into the membrane and open a pore at stoichiometries ranging from tetramers to full rings (~35 mers), whereby the rate of insertion increases linearly with the number of subunits. Oligomers that insert before the ring is complete continue to grow by monomer addition post insertion. Overall, our observations suggest that PFO membrane insertion is kinetically controlled.