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Abstract Emtricitabine (FTC) and lamivudine (3TC), containing an oxathiolane ring with unnatural (−)-stereochemistry, are widely used nucleoside reverse transcriptase inhibitors (NRTIs) in anti-HIV therapy. Treatment with FTC or 3TC primarily selects for the HIV-1 RT M184V/I resistance mutations. Here we provide a comprehensive kinetic and structural basis for inhibiting HIV-1 RT by (−)-FTC-TP and (−)-3TC-TP and drug resistance by M184V. (−)-FTC-TP and (−)-3TC-TP have higher binding affinities (1/Kd) for wild-type RT but slower incorporation rates than dCTP. HIV-1 RT ternary crystal structures with (−)-FTC-TP and (−)-3TC-TP corroborate kinetic results demonstrating that their oxathiolane sulfur orients toward the DNA primer 3′-terminus and their triphosphate exists in two different binding conformations. M184V RT displays greater (>200-fold)Kdfor theL-nucleotides and moderately higher (>9-fold)Kdfor theD-isomers compared to dCTP. The M184V RT structure illustrates how the mutation repositions the oxathiolane of (−)-FTC-TP and shifts its triphosphate into a non-productive conformation.
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Myelin figures from microbial glycolipid biosurfactant amphiphiles
Abstract Myelin figures (MFs)—cylindrical lyotropic liquid crystalline structures consisting of concentric arrays of bilayers and aqueous media—arise from the hydration of the bulk lamellar phase of many common amphiphiles. Prior efforts have concentrated on the formation, structure, and dynamics of myelin produced by phosphatidylcholine (PC)‐based amphiphiles. Here, we study the myelinization of glycolipid microbial amphiphiles, commonly addressed as biosurfactants, produced through the process of fermentation. The hydration characteristics (and phase diagrams) of these biological amphiphiles are atypical (and thus their capacity to form myelin) because unlike typical amphiphiles, their molecular structure is characterized by two hydrophilic groups (sugar, carboxylic acid) on both ends with a hydrophobic moiety in the middle. We tested three different glycolipid molecules: C18:1 sophorolipids and single‐glucose C18:1 and C18:0 glucolipids, all in their nonacetylated acidic form. Neither sophorolipids (too soluble) nor C18:0 glucolipids (too insoluble) displayed myelin growth at room temperature (RT, 25°C). The glucolipid C18:1 (G‐C18:1), on the other hand, showed dense myelin growth at RT below pH 7.0. Examining their growth rates, we find that they display a linear (L, myelin length;t, time) growth rate, suggesting ballistic growth, distinctly different from the dependence, characterizing diffusive growth such as what occurs in more conventional phospholipids. These results offer some insight into lipidic mesophases arising from a previously unexplored class of amphiphiles with potential applications in the field of drug delivery.
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- Award ID(s):
- 2104123
- PAR ID:
- 10555179
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Journal of Surfactants and Detergents
- Volume:
- 27
- Issue:
- 5
- ISSN:
- 1097-3958
- Format(s):
- Medium: X Size: p. 823-831
- Size(s):
- p. 823-831
- Sponsoring Org:
- National Science Foundation
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