Baylon, J. L. | Search bioRxiv

bioRxiv2021

PepSeA: Peptide Sequence Alignment and Visualization Tools to Enable Lead Optimization

Therapeutic peptides offer potential advantages over small molecules in terms of selectivity, affinity, and their ability to target "undruggable" proteins that are associated with a wide range of pathologies. Despite their importance, there are currently no adequate molecular design capabilities that inform medicinal chemistry decisions on peptide programs. More specifically, SAR (Structure-Activity Relationship) analysis and visualization of linear, cyclic, and cross-linked peptides containing non-natural motifs, which are widely used in drug discovery. To bridge this gap, we developed PepSeA (Peptide Sequence Alignment and Visualization), an open-source, freely available package of sequence-based tools (https://github.com/Merck/PepSeA). PepSeA enables multi-sequence alignment of non-natural amino acids and enhanced HELM (Hierarchical Editing Language for Macromolecules) visualization. Via stepwise SAR analysis of a ChEMBL peptide dataset, we demonstrate PepSeAs power to accelerate decision making in lead optimization campaigns in pharmaceutical settings. PepSeA represents an initial attempt to expand cheminformatics capabilities for therapeutic peptides and to enable rapid and more efficient design-make-test cycles.

bioinformatics↗

bioRxiv2020

Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel

The endocannabinoid (eCB) system is a promising target to mitigate pain as the eCBs are endogenous ligands of the pain-mediating receptors--cannabinoid receptors 1 and 2 (CB1 and CB2) and TRPV1. Here we report on a novel class of lipids formed by the epoxidation of N-arachidonoyl-dopamine (NADA) and N-arachidonoyl serotonin (NA5HT) by cytochrome P450 (CYP) epoxygenases. These epoxides (epoNADA and epoNA5HT) are dual-functional rheostat modulators (varying strength of agonism or antagonism) of the eCB-TRPV1 axis. In fact, epoNADA is a 6-fold stronger agonist of TRPV1 than NADA while epoNA5HT is a 30-fold stronger antagonist of TRPV1 than NA5HT and displays a significantly stronger inhibition on TRPV1-mediated responses in primary afferent neurons. Moreover, epoNA5HT is a full CB1 agonist. The epoxides reduce the pro-inflammatory biomarkers IL-6, IL-1{beta}, TNF- and nitrous oxide (NO) and raise anti-inflammatory IL-10 in activated microglial cells. The epoxides are spontaneously generated by activated microglia cells and their formation is potentiated in the presence of another eCB, anandamide (AEA). We provide evidence for the direct biochemical mechanism of this potentiation using human CYP2J2, a CYP epoxygenase in the human brain, using detailed kinetics studies and molecular dynamics simulations. Taken all together, inflammation leads to an increase in the metabolism of NADA, NA5HT and other eCBs by CYP epoxygenases to form the corresponding epoxides. The epoxide metabolites are bioactive lipids that are more potent, multi-faceted endogenous molecules, capable of influencing the activity of CB1, CB2 and TRPV1 receptors. The identification of these molecules will serve as templates for the synthesis of new multi-target therapeutics for the treatment of inflammatory pain.

biochemistry↗