Targeting of peptide‐binding receptors on cancer cells with peptide‐drug conjugates

Worm, Dennis J.; Els‐Heindl, Sylvia; Beck‐Sickinger, Annette G.

doi:10.1002/pep2.24171

Cited by 41 publications

(31 citation statements)

References 262 publications

(257 reference statements)

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“…The efficient internalization machinery of GPCRs can be used for cell‐specific drug delivery by peptide‐drug conjugates, which can be easily and site‐specifically equipped with different linker structures for intracellular cargo release 47–50 . Taking advantage of ligand‐induced internalization of GPCRs for intracellular cargo delivery has been demonstrated for targeting cancer‐related receptors like the gastrin‐releasing peptide receptor and the neuropeptide Y receptor 1 (Y 1 R) 51–53 .…”

Section: Discussionmentioning

confidence: 99%

The ring size of monocyclic ET‐1 controls selectivity and signaling efficiency at both endothelin receptor subtypes

Wolf

Beck‐Sickinger

2021

Journal of Peptide Science

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Cardiovascular diseases (CVDs) like hypertension are a major cause for death worldwide. In the cardiovascular tissue, the endothelin system—consisting of the receptor subtypes A (ETAR) and B (ETBR) and the mixed agonist endothelin 1 (ET‐1)—is a major key player in the regulation of vascular tone and blood pressure. Tight control of this system is required to maintain homeostasis; otherwise, the endothelin system can cause severe CVDs like pulmonary artery hypertension. The high sequence homology between both receptor subtypes limits the development of novel and selective ligands. Identification of small differences in receptor–ligand interactions and determination of selectivity constraints are crucial to fine‐tune ligand properties and subsequent signaling events. Here, we report on novel ET‐1 analogs and their detailed pharmacological characterization. We generated simplified ET‐1‐derived monocyclic peptides to provide an accessible synthesis route. By detailed in vitro characterization, we demonstrated that both G protein signaling and the subsequent arrestin recruitment of activated ETBR remain intact, whereas activation of the ETAR depends on the intramolecular ring size. Increasing of the intramolecular ring structure reduces activity at the ETAR and shifts the peptide toward ETBR selectivity. All ET‐1 analogs displayed efficient ETBR‐mediated signaling by G protein activation and arrestin 3 recruitment. Our study provides in‐depth characterization of the ET‐1/ETAR and ET‐1/ETBR interactions, which has the potential for future development of endothelin‐based drugs for CVD treatment. By identification of Lys9 for selective labeling, novel analogs for peptide‐mediated shuttling by ET‐1 are proposed.

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Section: Discussionmentioning

confidence: 99%

The ring size of monocyclic ET‐1 controls selectivity and signaling efficiency at both endothelin receptor subtypes

Wolf

Beck‐Sickinger

2021

Journal of Peptide Science

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“…Proteolytic degradation of peptide drugs by peptidase and rapid renal clearance can decrease their blood circulation time and limit their effectiveness (Fosgerau & Hoffmann, 2015). For the treatment of solid tumors, a longer circulation of PDCs is often required to allow sufficient time for delivery and penetration of the PDC into the malignant tissue (Worm et al, 2020). To overcome the unfavorable pharmacokinetics associated with PDCs, modern peptide chemistry including cyclization (e.g., octreotide), N ‐methylation, amino acid substitutions with unnatural or D‐amino acids, lipidation, terminal modification, and peptidomimetics have been investigated (Erak et al, 2018; Firer & Gellerman, 2012; Henninot et al, 2018; Lau & Dunn, 2018).…”

Section: Current Status and Challenges For Moving Pdc To Clinicmentioning

confidence: 99%

Brain penetrating peptides and peptide–drug conjugates to overcome the blood–brain barrier and target CNS diseases

Zhou

Smith

Liu

2021

WIREs Nanomed Nanobiotechnol

104

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Nearly one in six people worldwide suffer from disorders of the central nervous system (CNS). There is an urgent need for effective strategies to improve the success rates in CNS drug discovery and development. The lack of effective technologies for delivering drugs and genes to the brain due to the blood–brain barrier (BBB), a structural barrier that effectively blocks most neurotherapeutic agents from reaching the brain, has posed a formidable hurdle for CNS drug development. Brain‐homing and brain‐penetrating molecular transport vectors, such as brain permeable peptides or BBB shuttle peptides, have shown promise in overcoming the BBB and ferrying the drug molecules to the brain. The BBB shuttle peptides are discovered by phage display technology or derived from natural neurotropic proteins or certain viruses and harness the receptor‐mediated transcytosis molecular machinery for crossing the BBB. Brain permeable peptide–drug conjugates (PDCs), composed of BBB shuttle peptides, linkers, and drug molecules, have emerged as a promising CNS drug delivery system by taking advantage of the endogenous transcytosis mechanism and tricking the brain into allowing these bioactive molecules to pass the BBB. Here, we examine the latest development of brain‐penetrating peptide shuttles and brain‐permeable PDCs as molecular vectors to deliver small molecule drug payloads across the BBB to reach brain parenchyma. Emerging knowledge of the contribution of the peptides and their specific receptors expressed on the brain endothelial cells, choice of drug payloads, the design of PDCs, brain entry mechanisms, and delivery efficiency to the brain are highlighted. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease

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“…Many tumors overexpress one or more cell-surface markers like integrins [ 195 ], hormone receptors such as EGFRs [ 196 , 197 ], GPCRs [ 198 ] and immunoregulatory proteins [ 199 , 200 ]. Expression of surface markers on cancer cells provides an opportunity to selectively target them with peptides or peptidomimetics [ 201 , 202 ]. These cancer selective ligands (sometimes called tumor homing peptides) are usually, but not exclusively, implemented in a naked form as antagonists to their receptor molecules, and can also be used as carriers for targeted drug delivery (TDD) [ 203 , 204 ].…”

Section: Combination Of Drugs As Strategy To Achieve Better Clinicmentioning

confidence: 99%

Drug Combination in Cancer Treatment—From Cocktails to Conjugated Combinations

Gilad

Gellerman

Lonard

et al. 2021

Cancers

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It is well recognized today that anticancer drugs often are most effective when used in combination. However, the establishment of chemotherapy as key modality in clinical oncology began with sporadic discoveries of chemicals that showed antiproliferative properties and which as a first attempt were used as single agents. In this review we describe the development of chemotherapy from its origins as a single drug treatment with cytotoxic agents to polydrug therapy that includes targeted drugs. We discuss the limitations of the first chemotherapeutic drugs as a motivation for the establishment of combined drug treatment as standard practice in spite of concerns about frequent severe, dose limiting toxicities. Next, we introduce the development of targeted treatment as a concept for advancement within the broader field of small-molecule drug combination therapy in cancer and its accelerating progress that was boosted by recent scientific and technological progresses. Finally, we describe an alternative strategy of drug combinations using drug-conjugates for selective delivery of cytotoxic drugs to tumor cells that potentiates future improvement of drug combinations in cancer treatment. Overall, in this review we outline the development of chemotherapy from a pharmacological perspective, from its early stages to modern concepts of using targeted therapies for combinational treatment.

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Targeting of peptide‐binding receptors on cancer cells with peptide‐drug conjugates

Cited by 41 publications

References 262 publications

The ring size of monocyclic ET‐1 controls selectivity and signaling efficiency at both endothelin receptor subtypes

The ring size of monocyclic ET‐1 controls selectivity and signaling efficiency at both endothelin receptor subtypes

Brain penetrating peptides and peptide–drug conjugates to overcome the blood–brain barrier and target CNS diseases

Drug Combination in Cancer Treatment—From Cocktails to Conjugated Combinations

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