Delving into the Latest Updates on Lancovutide with Synapse

Overview

Basic Info

Drug Type

Synthetic peptide

Synonyms

Duramycin

+ [3]

Target

cPLA2α x chloride channel

Mechanism

cPLA2α inhibitors(Cytosolic phospholipase A2 inhibitors), chloride channel agonists(Chloride channel agonists)

Therapeutic Areas

Congenital DisordersDigestive System DisordersRespiratory Diseases+ [2]

Active Indication-

Inactive Indication

Cystic FibrosisDry Eye SyndromesPulmonary Disease, Chronic Obstructive+ [1]

Originator Organization

GSK Plc

Active Organization-

Inactive Organization

Aop Orphan Pharmaceuticals GmbHLantibio, Inc.

The University of North Carolina at Chapel Hill

+ [1]

Drug Highest PhasePendingPhase 3

First Approval Date-

RegulationOrphan Drug (EU)

Structure

Molecular FormulaC89H125N23O25S3

InChIKeySFWLDKQAUHFCBS-UHFFFAOYSA-N

CAS Registry1391-36-2

Gene Sequence

Sequence Code 525792052

AbstractThe continuous pursuit of designing an ideal infection imaging agent is a crucial and ongoing endeavor in the field of biomedical research. Duramycin, an antimicrobial peptide exerts its antimicrobial action on bacteria by specific recognition of phosphatidylethanolamine (PE) moiety present on most bacterial membranes, particularly Escherichia coli (E. coli). E. coli membranes contain more than 60% PE. Therefore, duramycin is an attractive candidate for the formulation of probes for in situ visualization of E. coli driven focal infections. The aim of the present study is to develop 99mTc labeled duramycin as a single‐photon emission computed tomography (SPECT)‐based agent to image such infections. Duramycin was successfully conjugated with a bifunctional chelator, hydrazinonicotinamide (HYNIC). PE specificity of HYNIC‐duramycin was confirmed by a dye release assay on PE‐containing model membranes. Radiolabeling of HYNIC–duramycin with 99mTc was performed with consistently high radiochemical yield (>90%) and radiochemical purity (>90%). [99mTc]Tc‐HYNIC‐duramycin retained its specificity for E. coli, in vitro. SPECT and biodistribution studies showed that the tracer could specifically identify E. coli driven infection at 3 h post injection. While 99mTc‐labeled duramycin is employed for monitoring early response to cancer therapy and cardiotoxicity, the current studies have confirmed, for the first time, the potential of utilizing 99mTc labeled duramycin as an imaging agent for detecting bacteria. Its application in imaging PE‐positive bacteria represents a novel and promising advancement.

01 Jul 2023·Redox Biology

Formation of protein adducts with Hydroperoxy-PE electrophilic cleavage products during ferroptosis

Article

Author: Kapralov, O ; Sparvero, L J ; Mikulska-Ruminska, K ; Anthonymuthu, T ; Bayir, H ; Shvedova, A A ; Bahar, I ; Tyurina, Y Y ; Wenzel, S ; Kagan, V E ; Shrivastava, I H ; Tyurin, V A ; Amoscato, A A

Ferroptosis is an iron dependent form of cell death, that is triggered by the discoordination of iron, lipids, and thiols. Its unique signature that distinguishes it from other forms of cell death is the formation and accumulation of lipid hydroperoxides, particularly oxidized forms of polyunsaturated phosphatidylethanolamines (PEs), which drives cell death. These readily undergo iron-catalyzed secondary free radical reactions leading to truncated products which retain the signature PE headgroup and which can readily react with nucleophilic moieties in proteins via their truncated electrophilic acyl chains. Using a redox lipidomics approach, we have identified oxidatively-truncated PE species (trPEox) in enzymatic and non-enzymatic model systems. Further, using a model peptide we demonstrate adduct formation with Cys as the preferred nucleophilic residue and PE(26:2) +2 oxygens, as one of the most reactive truncated PE-electrophiles produced. In cells stimulated to undergo ferroptosis we identified PE-truncated species with sn-2 truncations ranging from 5 to 9 carbons. Taking advantage of the free PE headgroup, we have developed a new technology using the lantibiotic duramycin, to enrich and identify the PE-lipoxidated proteins. Our results indicate that several dozens of proteins for each cell type, are PE-lipoxidated in HT-22, MLE, and H9c2 cells and M2 macrophages after they were induced to undergo ferroptosis. Pretreatment of cells with the strong nucleophile, 2-mercaptoethanol, prevented the formation of PE-lipoxidated proteins and blocked ferroptotic death. Finally, our docking simulations showed that the truncated PE species bound at least as good to several of the lantibiotic-identified proteins, as compared to the non-truncated parent molecule, stearoyl-arachidonoyl PE (SAPE), indicating that these oxidatively-truncated species favor/promote the formation of PEox-protein adducts. The identification of PEox-protein adducts during ferroptosis suggests that they are participants in the ferroptotic process preventable by 2-mercaptoethanol and may contribute to a point of no return in the ferroptotic death process.

16 May 2023·Proceedings of the National Academy of Sciences of the United States of AmericaQ1 · CROSS-FIELD

The DedA superfamily member PetA is required for the transbilayer distribution of phosphatidylethanolamine in bacterial membranes.

Q1 · CROSS-FIELD

Article

Author: Rudner, David Z ; Roney, Ian J

The sorting of phospholipids between the inner and outer leaflets of the membrane bilayer is a fundamental problem in all organisms. Despite years of investigation, most of the enzymes that catalyze phospholipid reorientation in bacteria remain unknown. Studies from almost half a century ago in Bacillus subtilis and Bacillus megaterium revealed that newly synthesized phosphatidylethanolamine (PE) is rapidly translocated to the outer leaflet of the bilayer [Rothman & Kennedy, Proc. Natl. Acad. Sci. U.S.A. 74, 1821-1825 (1977)] but the identity of the putative PE flippase has eluded discovery. Recently, members of the DedA superfamily have been implicated in flipping the bacterial lipid carrier undecaprenyl phosphate and in scrambling eukaryotic phospholipids in vitro. Here, using the antimicrobial peptide duramycin that targets outward-facing PE, we show that Bacillus subtilis cells lacking the DedA paralog PetA (formerly YbfM) have increased resistance to duramycin. Sensitivity to duramycin is restored by expression of B. subtilis PetA or homologs from other bacteria. Analysis of duramycin-mediated killing upon induction of PE synthesis indicates that PetA is required for efficient PE transport. Finally, using fluorescently labeled duramycin we demonstrate that cells lacking PetA have reduced PE in their outer leaflet compared to wildtype. We conclude that PetA is the long-sought PE transporter. These data combined with bioinformatic analysis of other DedA paralogs argue that the primary role of DedA superfamily members is transporting distinct lipids across the membrane bilayer.

1

News (Medical) associated with Lancovutide

11 May 2021

·www.biospace.com

Molecular Targeting Technologies, Inc. and University of Antwerp Begin First-in-Human Study of TDURA Diagnostic for Early Detection of Response to Colon Cancer Therapy

WEST CHESTER, Pa.--(BUSINESS WIRE)-- Molecular Targeting Technologies, Inc. (MTTI) and University of Antwerp today announced the approval of a Clinical Trial Application by the European Federal Agency for Medicines and Health Products (FAMHP) (equivalent to a US IND). The clinical study will evaluate the safety, dosimetry and treatment response of TDURA (99mTc-Duramycin), in patients with advanced colorectal cancer (CRC)*. Colorectal cancer is the third most commonly diagnosed malignancy in the world and the second leading cause of cancer death in the United States. While a range of novel active agents has improved the prognosis of patients with colorectal cancer, 50% of advanced colorectal cancer patients die from metastatic disease. Monitoring treatment efficacy early, within days, can significantly improve patient outcomes. Current diagnostic techniques can take weeks to months to gauge tumor killing drug efficacy. In some cases, treatment may only be effective in 40% of patients, leading to rapidly advancing cancer and higher costs while regrouping to change therapies. Duramycin, a naturally occurring peptide that binds to phosphatidylethanolamine (PE), has been radiolabeled and used for early imaging of tumor death in animal models. Professor Sigrid Stroobants, MD, Chair of Nuclear Medicine, U of Antwerp commented “Objective and accurate evaluation of tumor response to therapy is one of the biggest challenges in oncology. Early assessment of therapeutic ineffectiveness can avoid treatment related toxicity and could lead to improved survival through earlier treatment intensification, stopping the ineffective therapy, or starting second-line therapy.” Chris Pak, MTTI President & CEO said, “The most commonly used methods to evaluate the effectiveness of a treatment are morphological and volumetric which cannot see the effects of therapy early. If TDURA optimizes patient treatment, the benefits to the patients and savings to health care systems will be substantial.” UAntwerp-MICA was founded in 2010 as a joint effort by UAntwerp and UZA and has become one of the leaders in translating molecular imaging research from bench to patient, UAntwerp is not an island: it builds bridges to secondary education, to industry and, by extension, to society as a whole. With over 5,000 members of staff, UAntwerp is one of the most important employers in Antwerp, Flanders’ largest city. More information: Molecular Targeting Technologies, Inc. is a privately held, clinical stage biotechnology company, developing radiotherapeutics and diagnostics for cancers. MTTI has received an exclusive worldwide license from the National Institutes of Health to commercialize its EvaThera platform . MTTI is committed to building value by translating innovative imaging and theranostic assets to improve human health, reduce healthcare costs and reward stakeholders. More information: **Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R01CA226531. View source version on businesswire.com:

100 Deals associated with Lancovutide

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Cystic Fibrosis	Phase 3	CZ	Aop Orphan Pharmaceuticals GmbH	-
Cystic Fibrosis	Phase 3	HU	Aop Orphan Pharmaceuticals GmbH	-
Dry Eye Syndromes	Phase 3	US	Lantibio, Inc.	-
Pulmonary Disease, Chronic Obstructive	Phase 3	-	GSK Plc	-
Pulmonary Disease, Chronic Obstructive	Phase 3	-	The University of North Carolina at Chapel Hill	-
Pulmonary Disease, Chronic Obstructive	Phase 3	-	Aop Orphan Pharmaceuticals GmbH	-
Pulmonary Disease, Chronic Obstructive	Phase 3	-	Lantibio, Inc.	-
Xerophthalmia	Phase 3	-	Lantibio, Inc.	-
Xerophthalmia	Phase 3	-	The University of North Carolina at Chapel Hill	-
Xerophthalmia	Phase 3	-	GSK Plc	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ARVO2006	Phase 1	-	30	Moli1901 0.05%	(tzrkdeikjx) = There were no serious ocular or systemic adverse events. Twenty-four subjects (80%) reported at least one treatment-related adverse event, the majority of which were mild. Treatment-emergent adverse events judged possibly or probably related to treatment were predominantly eye related. The most frequently reported adverse events were corneal staining, conjunctival injection, and eye irritation. Corneal staining appeared to be dose related. flbfngbysf (wnwllegmnu ) View more	-	01 May 2006
				Moli1901 0.1%