Measurement of Λ_{b}^{0}, Λ_{c}^{+}, and Λ Decay Parameters Using Λ_{b}^{0}→Λ_{c}^{+}h^{-} Decays.

A comprehensive study of the angular distributions in the bottom-baryon decays Λ_{b}^{0}→Λ_{c}^{+}h^{-}(h=π,K), followed by Λ_{c}^{+}→Λh^{+} with Λ→pπ^{-} or Λ_{c}^{+}→pK_{S}^{0} decays, is performed using a data sample of proton-proton collisions corresponding to an integrated luminosity of 9  fb^{-1} collected by the LHCb experiment at center-of-mass energies of 7, 8, and 13 TeV. The decay parameters and the associated charge-parity (CP) asymmetries are measured, with no significant CP violation observed. For the first time, the Λ_{b}^{0}→Λ_{c}^{+}h^{-} decay parameters are measured.

Synthesis and Investigation of Peptide-Drug Conjugates Comprising Camptothecin and a Human Protein-Derived Cell-Penetrating Peptide.

Drug targeting strategies, such as peptide-drug conjugates (PDCs), have arisen to combat the issue of off-target toxicity that is commonly associated with chemotherapeutic small molecule drugs. Here we investigated the ability of PDCs comprising a human protein-derived cell-penetrating peptide-platelet factor 4-derived internalization peptide (PDIP)-as a targeting strategy to improve the selectivity of camptothecin (CPT), a topoisomerase I inhibitor that suffers from off-target toxicity. The intranuclear target of CPT allowed exploration of PDC design features required for optimal potency.

Highly Efficient Transpeptidase-Catalyzed Isopeptide Ligation.

Transpeptidases are specialized enzymes that have evolved for site-selective modification of peptides and proteins at their backbone termini. Approaches for adapting transpeptidases to catalyze side chain modifications are substantially more restricted, and typically rely on large recognition tags or require specific reaction conditions that are not easily compatible with broader applications. Here we show that the engineered asparaginyl ligase AEP1 catalyzes direct isopeptide ligation by accepting an internal 2,3-diaminopropionic acid (Dap) residue adjacent to Leu, a motif that mimics the canonical N-terminal Gly-Leu substrate.

Exploring the Utility of Cell-Penetrating Peptides as Vehicles for the Delivery of Distinct Antimalarial Drug Cargoes.

The devastating impact of malaria includes significant mortality and illness worldwide. Increasing resistance of the causative parasite, Plasmodium, to existing antimalarial drugs underscores a need for additional compounds with distinct modes of action in the therapeutic development pipeline. Here we showcase peptide-drug conjugates (PDCs) as an attractive compound class, in which therapeutic or lead antimalarials are chemically conjugated to cell-penetrating peptides.

Search for Time-Dependent CP Violation in D^{0}→π^{+}π^{-}π^{0} Decays.

A measurement of time-dependent CP violation in D^{0}→π^{+}π^{-}π^{0} decays using a pp collision data sample collected by the LHCb experiment in 2012 and from 2015 to 2018, corresponding to an integrated luminosity of 7.7  fb^{-1}, is presented. The initial flavor of each D^{0} candidate is determined from the charge of the pion produced in the D^{*}(2010)^{+}→D^{0}π^{+} decay.

Recombinant Production of The Cyclotide Kalata B1 by Conditional Split Inteins.

This study describes the design, production, and characterization of a novel conditional intein system for the recombinant production of cyclic peptides. The system is based on two key features: (1) a promiscuous extein recognition site allowing cyclization of virtually any peptide, and (2) a secondary split site within the intein itself enabling triggered splicing at will. Two intein precursors were recombinantly expressed, purified, and then self-assembled in vitro to cyclize the model peptide kalata B1 (kB1).

The prospect of substrate-based kinase inhibitors to improve target selectivity and overcome drug resistance.

Human kinases are recognized as one of the most important drug targets associated with cancer. There are >80 FDA-approved kinase inhibitors to date, most of which work by inhibiting ATP binding to the kinase. However, the frequent development of single-point mutations within the kinase domain has made overcoming drug resistance a major challenge in drug discovery today.

Peptide PaDBS1R6 has potent antibacterial activity on clinical bacterial isolates and integrates an immunomodulatory peptide fragment within its sequence.

Background: Resistant infectious diseases caused by gram-negative bacteria are among the most serious worldwide health problems. Antimicrobial peptides (AMPs) have been explored as promising antibacterial, antibiofilm, and anti-infective candidates to address these health challenges.

Major Conclusions: Here we report the potent antibacterial effect of the peptide PaDBS1R6 on clinical bacterial isolates and identify an immunomodulatory peptide fragment incorporated within it.

Hijacking of N-fixing legume albumin-1 genes enables the cyclization and stabilization of defense peptides.

The legume albumin-1 gene family, arising after nodulation, encodes linear a- and b-chain peptides for nutrient storage and defense. Intriguingly, in one prominent legume, Clitoria ternatea, the b-chains are replaced by domains producing ultra-stable cyclic peptides called cyclotides. The mechanism of this gene hijacking is until now unknown.

Enhancing the Intrinsic Antiplasmodial Activity and Improving the Stability and Selectivity of a Tunable Peptide Scaffold Derived from Human Platelet Factor 4.

The control of malaria, a disease caused by parasites that kills over half a million people every year, is threatened by the continual emergence and spread of drug resistance. Therefore, new molecules with different mechanisms of action are needed in the antimalarial drug development pipeline. Peptides developed from host defense molecules are gaining traction as anti-infectives due to theood of inducing drug resistance.

Cyclic tachyplesin I kills proliferative, non-proliferative and drug-resistant melanoma cells without inducing resistance.

Acquired drug resistance is the major cause for disease recurrence in cancer patients, and this is particularly true for patients with metastatic melanoma that carry a BRAF mutation. To address this problem, we investigated cyclic membrane-active peptides as an alternative therapeutic modality to kill drug-tolerant and resistant melanoma cells to avoid acquired drug resistance. We selected two stable cyclic peptides (cTI and cGm), previously shown to have anti-melanoma properties, and compared them with dabrafenib, a drug used to treat cancer patients with the BRAF mutation.

Modification of χ_{c1}(3872) and ψ(2S) Production in pPb Collisions at sqrt[s_{NN}]=8.16 TeV.

The LHCb Collaboration measures production of the exotic hadron χ_{c1}(3872) in proton-nucleus collisions for the first time. Comparison with the charmonium state ψ(2S) suggests that the exotic χ_{c1}(3872) experiences different dynamics in the nuclear medium than conventional hadrons, and comparison with data from proton-proton collisions indicates that the presence of the nucleus may modify χ_{c1}(3872) production rates. This is the first measurement of the nuclear modification factor of an exotic hadron.

Conotoxins Targeting Voltage-Gated Sodium Ion Channels.

Voltage-gated sodium (Na) channels are intimately involved in the generation and transmission of action potentials, and dysfunction of these channels may contribute to nervous system diseases, such as epilepsy, neuropathic pain, psychosis, autism, and cardiac arrhythmia. Many venom peptides selectively act on Na channels. These include conotoxins, which are neurotoxins secreted by cone snails for prey capture or self-defense but which are also valuable pharmacological tools for the identification and/or treatment of human diseases.

Chemical synthesis of grafted cyclotides using a "plug and play" approach.

Cyclotides are a diverse class of plant-derived cyclic, disulfide-rich peptides with a unique cyclic cystine knot topology. Their remarkable structural stability and resistance to proteolytic degradation can lead to improved pharmacokinetics and oral activity as well as selectivity and high enzymatic stability. Thus, cyclotides have emerged as powerful scaffold molecules for designing peptide-based therapeutics.

Design, Synthesis, and Structure-Activity Relationships of Novel Peptide Derivatives of the Severe Acute Respiratory Syndrome-Coronavirus-2 Spike-Protein that Potently Inhibit Nicotinic Acetylcholine Receptors.

The spike-protein of SARS-CoV-2 has a distinctive amino-acid sequence (RRARS) that forms a cleavage site for the enzyme furin. Strikingly, the structure of the spike-protein loop containing the furin cleavage site bears substantial similarity to neurotoxin peptides found in the venoms of certain snakes and marine cone snails. Leveraging this relationship, we designed and synthesized disulfide-constrained peptides with amino-acid sequences corresponding to the furin cleavage-sites of wild-type (B.

Repurposing a plant peptide cyclase for targeted lysine acylation.

Transpeptidases are powerful tools for protein engineering but are largely restricted to acting at protein backbone termini. Alternative enzymatic approaches for internal protein labelling require bulky recognition motifs or non-proteinogenic reaction partners, potentially restricting which proteins can be modified or the types of modification that can be installed. Here we report a strategy for labelling lysine side chain ε-amines by repurposing an engineered asparaginyl ligase, which naturally catalyses peptide head-to-tail cyclization, for versatile isopeptide ligations that are compatible with peptidic substrates.

Aspartic acid mutagenesis of αO-Conotoxin GeXIVA isomers reveals arginine residues crucial for inhibition of the α9α10 nicotinic acetylcholine receptor.

The two most active disulfide bond isomers of the analgesic αO-conotoxin GeXIVA, namely GeXIVA[1, 2] and GeXIVA[1, 4], were subjected to Asp-scanning mutagenesis to determine the key amino acid residues for activity at the rat α9α10 nicotinic acetylcholine receptor (nAChR). These studies revealed the key role of arginine residues for the activity of GeXIVA isomers towards the α9α10 nAChR. Based on these results, additional analogues with 2-4 mutations were designed and tested.

Isolation and Characterization of Insecticidal Cyclotides from .

Cyclotides are cysteine-rich plant-derived peptides composed of 28-37 amino acids with a head-to-tail cyclic backbone and a knotted arrangement of three conserved disulfide bonds. Their beneficial biophysical properties make them promising molecules for pharmaceutical and agricultural applications. The Violaceae plant family is the major cyclotide-producing family, and to date, every examined plant from this family has been found to contain cyclotides.

Seasonal tissue-specific gene expression in wild crown-of-thorns starfish reveals reproductive and stress-related transcriptional systems.

Animals are influenced by the season, yet we know little about the changes that occur in most species throughout the year. This is particularly true in tropical marine animals that experience relatively small annual temperature and daylight changes. Like many coral reef inhabitants, the crown-of-thorns starfish (COTS), well known as a notorious consumer of corals and destroyer of coral reefs, reproduces exclusively in the summer.

Structure and Activity of Reconstructed Pseudo-Ancestral Cyclotides.

Cyclotides are cyclic peptides that are promising scaffolds for the design of drug candidates and chemical tools. However, despite there being hundreds of reported cyclotides, drug design studies have commonly focussed on a select few prototypic examples. Here, we explored whether ancestral sequence reconstruction could be used to generate new cyclotides for further optimization.