Torrey Pines Institute for Molecular Studies

About: Torrey Pines Institute for Molecular Studies is a nonprofit organization based out in San Diego, California, United States. It is known for research contribution in the topics: T cell & Antigen. The organization has 2323 authors who have published 2217 publications receiving 112618 citations.

N-acylated peptides derived from human lactoferricin perturb organization of cardiolipin and phosphatidylethanolamine in cell membranes and induce defects in Escherichia coli cell division.

Abstract: Two types of recently described antibacterial peptides derived from human lactoferricin, either nonacylated or N-acylated, were studied for their different interaction with membranes of Escherichia coli in vivo and in model systems Electron microscopy revealed striking effects on the bacterial membrane as both peptide types induced formation of large membrane blebs Electron and fluorescence microscopy, however demonstrated that only the N-acylated peptides partially induced the generation of oversized cells, which might reflect defects in cell-division Further a different distribution of cardiolipin domains on the E coli membrane was shown only in the presence of the N-acylated peptides The lipid was distributed over the whole bacterial cell surface, whereas cardiolipin in untreated and nonacylated peptide-treated cells was mainly located at the septum and poles Studies with bacterial membrane mimics, such as cardiolipin or phosphatidylethanolamine revealed that both types of peptides interacted with the negatively charged lipid cardiolipin The nonacylated peptides however induced segregation of cardiolipin into peptide-enriched and peptide-poor lipid domains, while the N-acylated peptides promoted formation of many small heterogeneous domains Only N-acylated peptides caused additional severe effects on the main phase transition of liposomes composed of pure phosphatidylethanolamine, while both peptide types inhibited the lamellar to hexagonal phase transition Lipid mixtures of phosphatidylethanolamine and cardiolipin revealed anionic clustering by all peptide types However additional strong perturbation of the neutral lipids was only seen with the N-acylated peptides Nuclear magnetic resonance demonstrated different conformational arrangement of the N-acylated peptide in anionic and zwitterionic micelles revealing possible mechanistic differences in their action on different membrane lipids We hypothesized that both peptides kill bacteria by interacting with bacterial membrane lipids but only N-acylated peptides interact with both charged cardiolipin and zwitterionic phosphatidylethanolamine resulting in remodeling of the natural phospholipid domains in the E coli membrane that leads to defects in cell division

Interrogating Novel Areas of Chemical Space for Drug Discovery using Chemoinformatics

Abstract: Preclinical Research Chemoinformatic approaches have an essential role in the systematic description and visualization of the chemical space for drug discovery projects. These methods enable the quantitative comparison of general screening collections and the systematic classification of approved drugs and databases annotated with biological activity to define biologically and medicinally relevant chemical spaces. Profiling of chemical diversity, molecular complexity, and physicochemical properties of compound libraries using chemoinformatic approaches provide a solid basis to generate hypothesis of how to interrogate novel areas of chemical space for enhanced drug discovery. This commentary is focused on the application of chemoinformatic approaches to mine, and to navigate the chemical space of compound collections. The discussion is centered on the concept of chemical space, types of compound libraries used in drug discovery programs, applications of chemical space mining and visualization using chemoinformatic methods, and strategies to expand the pharmaceutical relevant chemical space with emphasis on the notion of molecular complexity.

MEIC evaluation of acute systemic toxicity. Part III. In vitro results from 16 additional methods used to test the first 30 reference chemicals and a comparative cytotoxicity analysis

Abstract: Results from tests on the first 30 MEIC reference chemicals in 16 different systems are presented as a prerequisite to the subsequent in vitro/in vivo comparisons of acute toxicity data, i.e. the final MEIC evaluation of all test results of the study. The study is a supplement to the previously published results from 68 methods (including methods 45B and 46B [old numbers]) used to test the same set of chemicals. The strategies and methods of the preceding paper were employed to enable a comparative cytotoxicity analysis of the results from these 68 methods and from the 16 new methods to be made. Principal components analysis (PCA) of 82 assays demonstrated a dominating first component which described as much as 83% of the variance in the toxicity data. This remarkable similarity of all toxicity data was the main finding of the present study, and confirmed the results of the previous study with a less-extensive database. Also, the influence on the general variability of results of several key methodological factors was evaluated by analysis of selected sets of data, including linear regression of the results of pairs of methods, which were similar in all respects except for the factor under analysis. This analysis of the same 82 assays as before also confirmed previous results from the 68 assay database: a) the toxicities of a third of the chemicals increased considerably with exposure time; b) in general, cytotoxicity for human cells was well predicted by cytotoxicity tests with animal cells; c) this prediction was poor for two chemicals, i.e. digoxin and malathion; d) prediction of human cytotoxicity by ecotoxicological tests was only fairly good; e) 25 comparisons of similar assays employing different cell lines showed strikingly similar toxicities (mean R2 = 0.86); f) 22 comparisons of similar pairs of assays employing different primary cultures and cell lines also revealed similar toxicities (mean R2 = 0.79); and g) 15 comparisons of similar assays with different growth/viability endpoint measurements demonstrated strikingly similar toxicities (mean R2 = 0.89). Results b, e, f and g must be the main causes of the general similarity of results, while results a, c and d, together with other factors, could explain the 20% dissimilarity. These findings support the basal cytotoxicity concept and may assist in guiding and refining in vitro toxicity testing in the future.

Unexpected Opioid Activity Profiles of Analogues of the Novel Peptide Kappa Opioid Receptor Ligand CJ‐15,208

Abstract: An alanine scan was performed on the novel κ opioid receptor (KOR) peptide ligand CJ-15,208 to determine which residues contribute to the potent in vivo agonist activity observed for the parent peptide. These cyclic tetrapeptides were synthesized by a combination of solid-phase peptide synthesis of the linear precursors, followed by cyclization in solution. Like the parent peptide, each of the analogues exhibited agonist activity and KOR antagonist activity in an antinociceptive assay in vivo. Unlike the parent peptide, the agonist activity of the potent analogues was mediated predominantly, if not exclusively, by μ opioid receptors (MOR). Thus analogues 2 and 4, in which one of the phenylalanine residues was replaced by alanine, exhibited both potent MOR agonist activity and KOR antagonist activity in vivo. These peptides represent novel lead compounds for the development of peptide-based opioid analgesics.

Synthetic α-Conotoxin Mutants as Probes for Studying Nicotinic Acetylcholine Receptors and in the Development of Novel Drug Leads

Abstract: α-Conotoxins are peptide neurotoxins isolated from venomous marine cone snails that are potent and selective antagonists for different subtypes of nicotinic acetylcholine receptors (nAChRs). As such, they are valuable probes for dissecting the role that nAChRs play in nervous system function. In recent years, extensive insight into the binding mechanisms of α-conotoxins with nAChRs at the molecular level has aided in the design of synthetic analogs with improved pharmacological properties. This review examines the structure-activity relationship studies involving α-conotoxins as research tools for studying nAChRs in the central and peripheral nervous systems and their use towards the development of novel therapeutics.