Biology subjects

Pogostin, B. H.

Publications and source records attributed to Pogostin, B. H..

3 recordsLinked to original sources

bioRxiv2024

Enhanced dynamic covalent chemistry for the controlled release of small molecules and biologics from a nanofibrous peptide hydrogel platform

Maintaining safe and potent pharmaceutical drug levels is often challenging. Multidomain peptides (MDPs) assemble into supramolecular hydrogels with a well-defined, highly porous nanostructure that makes them attractive for drug delivery, yet their ability to extend release is typically limited by rapid drug diffusion. To overcome this challenge, we developed self-assembling boronate ester release (SABER) MDPs capable of engaging in dynamic covalent bonding with payloads containing boronic acids (BAs). As examples, we demonstrate that SABER hydrogels can prolong the release of five BA-containing small-molecule drugs as well as BA-modified insulin and antibodies. Pharmacokinetic studies revealed that SABER hydrogels extended the therapeutic effect of ganfeborole from days to weeks, preventing Mycobacterium tuberculosis growth better than repeated oral administration in an infection model. Similarly, SABER hydrogels extended insulin activity, maintaining normoglycemia for six days in diabetic mice after a single injection. These results suggest that SABER hydrogels present broad potential for clinical translation.

bioengineering↗

bioRxiv2024

Heterotrimeric Collagen Helix with High Specificity of Assembly Results in a Rapid Rate of Folding

The most abundant natural collagens form heterotrimeric triple helices. Synthetic mimics of collagen heterotrimers have been found to fold slowly, even compared to the already slow rates of homotrimeric helices. These prolonged folding rates are not understood and have not been studied. This work compares three heterotrimeric collagen mimics stabilities, specificities and folding rates. One of these was designed through a computational-assisted approach, resulting in a well-controlled composition and register, in addition to providing increased amino acid diversity and excellent specificity. The crystal structure of this heterotrimer elucidates the composition, register and geometry of pairwise cation-{pi} and axial and lateral salt bridges. Complementary experimental methods of circular dichroism and NMR suggest the folding paradigm is frustrated by unproductive, competing heterotrimer species and these species must completely unwind to the monomeric state before refolding into the thermodynamically favored assembly. This collagen heterotrimer, which displays the best reported thermal specificity, was also found to fold much faster (hours vs days) than comparable, well-designed systems. The heterotrimeric collagen folding rate was observed to be both concentration and temperature-independent, suggesting a complex, multi-step mechanism. These results suggest heterotrimer folding kinetics are dominated by frustration of the energy landscape caused by competing triple helices.

biophysics↗

bioRxiv2024

A TLR7 Agonist Conjugated to a Nanofibrous Peptide Hydrogel as a Potent Vaccine Adjuvant

Toll-like receptors (TLRs) recognize pathogen- and damage-associated molecular patterns and, in turn, trigger the release of cytokines and other immunostimulatory molecules. As a result, TLR agonists are increasingly being investigated as vaccine adjuvants, though many of these agonists are small molecules that quickly diffuse away from the vaccination site, limiting their co-localization with antigens and, thus, their effect. Here, the small-molecule TLR7 agonist 1V209 is conjugated to a positively-charged multidomain peptide (MDP) hydrogel, K2, which was previously shown to act as an adjuvant promoting humoral immunity. Mixing the 1V209-conjugated K2 50:50 with the unfunctionalized K2 produces hydrogels that retain the shear-thinning and self-healing physical properties of the original MDP, while improving the solubility of 1V209 more than 200-fold compared to the unconjugated molecule. When co-delivered with ovalbumin as a model antigen, 1V209-functionalized K2 produces antigen-specific IgG titers that were statistically similar to alum, the gold standard adjuvant, and a significantly lower ratio of Th2-associated IgG1 to Th1-associated IgG2a than alum, suggesting a more balanced Th1 and Th2 response. Together, these results suggest that K2 MDP hydrogels functionalized with 1V209 are a promising adjuvant for vaccines against infectious diseases, especially those benefiting from a combined Th1 and Th2 immune response. Table of ContentsActivation of toll-like receptors (TLRs) stimulates a signaling cascade to induce an immune response. A TLR7 agonist was conjugated to an injectable peptide hydrogel, which was then used to deliver a model vaccine antigen. This platform produced antibody titers similar to the gold standard adjuvant alum and demonstrated an improved balance between Th1- and Th2-mediated immunity over alum. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/583938v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@f546eeorg.highwire.dtl.DTLVardef@103e3f6org.highwire.dtl.DTLVardef@6b48b8org.highwire.dtl.DTLVardef@1733fd7_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗