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COVID-19 is a pandemic with high morbidity and mortality. In an autopsy cohort of COVID-19 patients, we found extensive accumulation of the tryptophan degradation products 3-hydroxy-anthranilic acid and quinolinic acid in the lungs, heart, and brain. This was not related to the expression of the tryptophan-catabolizing indoleamine 2,3-dioxygenase (IDO)-1, but rather to that of its isoform IDO-2, which otherwise is expressed rarely. Bioavailability of tryptophan is an absolute requirement for proper cell functioning and synthesis of hormones, whereas its degradation products can cause cell death. Markers of apoptosis and severe cellular stress were associated with IDO-2 expression in large areas of lung and heart tissue, whereas affected areas in brain were more restricted. Analyses of tissue, cerebrospinal fluid, and sequential plasma samples indicate early initiation of the kynurenine/aryl-hydrocarbon receptor/IDO-2 axis as a positive feedback loop, potentially leading to severe COVID-19 pathology. © 2021 The Authors. The Journal of Pathology published by John WileySons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Following a biomimetic approach, synthetic polypeptides designed to induce porphyrin self-assembly into nanostructures were created. Because of their stability and favorable spectroscopic properties, peptide-porphyrin aggregates could be applied as light harvesting antennas in dye-sensitized nanocrystalline solar cells. Using a designed porphyrin binding motif (PBM) consisting of 3 cationic lysine residues, we have developed and characterized a short, amphiphilic peptide that can efficiently bind three meso-tetra (4-sulfonatophenyl) porphine (TPPS) molecules and facilitate three-dimensional orientation into an excitonically coupled J-aggregate. The ability of the peptide to act as a scaffold for TPPS interactions was shown to be dependent on the sample pH and the resulting impacts on peptide secondary structure conformation using a combination of fluorescence, absorbance and circular dichroism spectroscopy. Under all conditions tested the peptide was shown to cooperatively bind three TPPS molecules per peptide with little change in Kd from pH 1.8 through 7.6. At low pH (3.6 and below) the peptide adopted a random coil conformation and allowed for the TPPS molecules to form the J-aggregate structure. Upon neutralization of the sample pH, the peptide adopts a predominantly alpha-helical structure which is concomitant with the loss of J-aggregate formation within the TPPS molecules. Using a series of peptides that contained Trp at different positions with respect to the PBMs we have initial measures of the sequence specificity of the cooperative binding event in terms of which PBM sequence is more likely to be the FIRST in the peptide to bind a TPPS molecule.

Antimicrobial peptides are a class of short, amphiphilic peptides which are part of the innate immune system of most higher organisms. These molecules act as a first line of defense against bacterial infection, exhibiting selective recognition of bacterial pathogens over host cells and rapid killing kinetics. The studies presented focus on the antimicrobial peptide C18G which is derived from the c-terminal sequence of a human platelet factor protein. This peptide has shown high efficacy in the low micromolar range against both gram-positive and gram-negative species which was maintained upon an amino acid substitution to facilitate monitoring via fluorescence spectroscopy (Y3W). The initial experiments focused on the binding affinities of sequence-substituted C18G variants in which the cationic Lysine residues were replaced with either Arginine or Histidine. All variants of the peptide exhibited high affinity for lipid membranes that contain anionic lipids (PG or PS) and a significant decrease in affinity for bilayers composed only of zwitterionic lipids (PC or PC/PE mixtures). All peptides exhibited similar binding affinities when the solution pH was lowered to pH4 or raised to pH10, indicative of a multi-component binding. Additionally, all peptides were shown to adopt a predominantly alpha-helical conformation when bound to lipid vesicles or detergent micelles. A dramatically different profile was observed when these peptides were were tested for bacterial membrane permeabilization. The Lys and Arg variants exhibited an expected dose-dependent permeabilization of both the outer and inner membranes of E.coli while the His variant showed no increase in membrane permeability. This pattern held true for the disruption of S.aureus membrane potential by the same set of peptides. These results are indicative of decoupling the binding and killing events which argues against a nonspecific, membrane aggregate mechanism of action.