Molecular Display of the Animal Meta-Venome for Discovery of Novel Therapeutic Peptides.

Animal venoms, distinguished by their unique structural features and potent bioactivities, represent a vast and relatively untapped reservoir of therapeutic molecules. However, limitations associated with extracting or expressing large numbers of individual venoms and venom-like molecules have precluded their therapeutic evaluation via high throughput screening. Here, we developed an innovative computational approach to design a highly diverse library of animal venoms and "metavenoms". We employed programmable M13 hyperphage display to preserve critical disulfide-bonded structures for highly parallelized single-round biopanning with quantitation via high-throughput DNA sequencing. Our approach led to the discovery of Kunitz type domain containing proteins that target the human itch receptor Mas-related G protein-coupled receptor X4 (MRGPRX4), which plays a crucial role in itch perception. Deep learning-based structural homology mining identified two endogenous human homologs, tissue factor pathway inhibitor (TFPI) and serine peptidase inhibitor, Kunitz type 2 (SPINT2), which exhibit agonist-dependent potentiation of MRGPRX4. Highly multiplexed screening of animal venoms and metavenoms is therefore a promising approach to uncover new drug candidates.

Comparison of the Impacts of Under-Treated Pain and Opioid Pain Medication on Cognitive Impairment.

PURPOSE: To guide clinicians in balancing the risks and benefits of opioids when treating pain, we conducted two systematic reviews: 1) the impact of pain on cognitive function, and 2) the impact of opioids on cognitive function. METHODS: Part one addressed the impact of pain on cognitive impairment; Part two considered the impact of opioids on cognitive impairment. PubMed was used to search for eligible articles. For part one, 1786 articles were identified, of which 23 met our eligibility criteria. For part two, among 584 articles, 18 were found eligible. RESULTS: For part one, 16 studies concluded that patients with chronic pain showed impaired cognitive function; six studies found that chronic pain does not worsen cognitive function; one study concluded that the impact of pain on cognitive function differs based on the underlying cognitive status. For part two, 15 studies found that using opioids to control pain did not cause significant cognitive impairment, while three studies concluded the opposite. Studies evaluating older subjects did not observe different results from those in the whole population for both reviews. CONCLUSION: The published literature indicates that moderate to severe pain can impair cognitive function, and that careful use of opioid analgesics in such subjects does not necessarily worsen cognition. Although our results are insufficient to support clear guidance due to heterogeneity of cohorts and outcomes, this study may assist primary care providers by rendering explicitly the factors to be considered by providers caring for this population with pain when opioids are considered.