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1.
Methods Mol Biol ; 2329: 39-50, 2021.
Article in English | MEDLINE | ID: mdl-34085214

ABSTRACT

Fluorescent biosensors can report on the relative abundance, activity, or conformation of biomolecules and analytes through changes in fluorescence emission. A wide variety of genetically-encoded and synthetic biosensors have been developed to monitor protein kinase activity. We have focused on the design, engineering and characterization of fluorescent peptide biosensors of cyclin-dependent kinases (CDKs) that constitute attractive cancer biomarkers and pharmacological targets. In this chapter, we describe the CDKACT fluorescent peptide biosensor technology and its application to assess the relative kinase activity of CDKs in vitro, either using recombinant proteins or cell extracts as a more complex source of kinase. This technology offers a straightforward means of comparing CDK activity in different cell lines and evaluating the specific impact of treatments intended to target kinase activity in a physiologically relevant environment.


Subject(s)
Cell Extracts/analysis , Cyclin-Dependent Kinases/analysis , Fluorescent Dyes/chemistry , Biosensing Techniques , Cell Line , Cyclin-Dependent Kinases/chemistry , Genetic Engineering , Humans
2.
Small ; 17(7): e2007177, 2021 02.
Article in English | MEDLINE | ID: mdl-33502119

ABSTRACT

Probing the dynamics and quantifying the activities of intracellular protein kinases that coordinate cell growth and division and constitute biomarkers and pharmacological targets in hyperproliferative and pathological disorders remain a challenging task. Here engineering and characterization of a nanobiosensor of the mitotic kinase CDK1, through multifunctionalization of carbon nanotubes with a CDK1-specific fluorescent peptide reporter, are described. This original reporter of CDK1 activity combines the sensitivity of a fluorescent biosensor with the unique physico-chemical and biological properties of nanotubes for multifunctionalization and efficient intracellular penetration. The functional versatility of this nanobiosensor enables implementation to quantify CDK1 activity in a sensitive and dose-dependent fashion in complex biological environments in vitro, to monitor endogenous kinase in living cells and directly within tumor xenografts in mice by fluorescence imaging, thanks to a ratiometric quantification strategy accounting for response relative to concentration in space and in time.


Subject(s)
CDC2 Protein Kinase , Nanotubes, Carbon , Neoplasms, Experimental/enzymology , Animals , CDC2 Protein Kinase/metabolism , Cell Line, Tumor , Humans , Mice , Phosphorylation
3.
Chembiochem ; 22(6): 1065-1071, 2021 03 16.
Article in English | MEDLINE | ID: mdl-33112024

ABSTRACT

CDK6 kinase regulates cell-cycle progression in G1, together with CDK4, but has cell-, tissue- and developmentally distinct functions associated with transcription, angiogenesis and metabolism. Although CDK6 makes an attractive cancer biomarker and target, there are no means of assessing its activity in a complex environment. In this study, we describe the design, engineering and characterisation of a fluorescent peptide biosensor derived from 6-phosphofructokinase that reports on CDK6 kinase activity through sensitive changes in fluorescence intensity. This biosensor can report on CDK6 activity in a dose-dependent fashion, thereby enabling quantification of differences in kinase activity in complex and physiologically relevant environments. Further implementation of this biosensor in different lung and melanoma cell lines, as well as in mesothelioma cell lines derived from patients together with a CDK4 biosensor highlighted differences in kinase activity between CDK6 and CDK4 kinase. This work demonstrates the utility of these selective tools for monitoring two closely related kinases comparatively and simultaneously in the same samples, thereby offering attractive perspectives for diagnostic and therapeutic purposes.


Subject(s)
Biosensing Techniques/methods , Cyclin-Dependent Kinase 6/metabolism , Fluorescent Dyes/chemistry , Peptides/metabolism , Amino Acid Sequence , Cell Extracts/chemistry , Cell Line, Tumor , Cyclin-Dependent Kinase 4/genetics , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/genetics , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mesothelioma/metabolism , Mesothelioma/pathology , Peptides/chemistry , Recombinant Proteins/biosynthesis , Recombinant Proteins/isolation & purification , Rhodamines/chemistry , Spectrometry, Fluorescence
4.
Front Chem ; 8: 691, 2020.
Article in English | MEDLINE | ID: mdl-32974274

ABSTRACT

CDK5/p25 kinase plays a major role in neuronal functions, and is hyperactivated in several human cancers including glioblastoma and neurodegenerative pathologies such as Alzheimer's and Parkinson's. CDK5 therefore constitutes an attractive pharmacological target. Since the successful discovery and development of Roscovitine, several ATP-competitive inhibitors of CDK5 and peptide inhibitors of CDK5/p25 interface have been developed. However, these compounds suffer limitations associated with their mechanism of action and nature, thereby calling for alternative targeting strategies. To date, few allosteric inhibitors have been developed for successful targeting of protein kinases. Indeed, although this latter class of inhibitors are believed to be more selective than compounds targeting the active site, they have proven extremely difficult to identify in high throughput screens. By implementing a fluorescent biosensor that discriminates against ATP-pocket binding compounds to screen for allosteric inhibitors that target conformational activation of CDK5, we have identified a novel family of quinazolinones. Characterization of these hits and several of their derivatives revealed their inhibitory potential toward CDK5 kinase activity in vitro and to inhibit glioblastoma cell proliferation. The quinazolinone derivatives described in this study are the first small molecules reported to target CDK5 at a site other than the ATP pocket, thereby constituting attractive leads for glioblastoma therapeutics and providing therapeutic perspectives for neurodegenerative diseases. These compounds offer alternatives to conventional ATP-competitive inhibitors or peptides targeting CDK5/p25 interface with the potential of bypassing their limitations.

5.
Biotechnol J ; 15(9): e1900474, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32379380

ABSTRACT

CDK5 plays a major role in neuronal functions, and is hyperactivated in neurodegenerative pathologies as well as in glioblastoma and neuroblastoma. Although this kinase constitutes an established biomarker and pharmacological target, there are few means of probing its activity in cell extracts or in living cells. To this aim a fluorescent peptide reporter of CDK5 kinase activity, derived from a library of CDK5-specific substrates, is engineered and its ability to respond to recombinant CDK5/p25 is established and CDK5 activity in glioblastoma cell extracts is reported on through sensitive changes in fluorescence intensity. A cell-penetrating variant of this biosensor which can be implemented to image CDK5 activation dynamics in space and in time is further implemented. This original biosensor constitutes a potent tool for quantifying differences in CDK5 activity following treatment with selective inhibitors and for monitoring CDK5 activation, following inhibition or stimulation, in a physiologically relevant environment. As such it offers attractive opportunities to develop a diagnostic assay for neuronal pathologies associated with hyperactivated CDK5, as well as a companion assay to evaluate response to new therapies targeting this kinase.


Subject(s)
Biosensing Techniques , Glioblastoma , Cell Extracts , Glioblastoma/genetics , Humans , Neurons , Phosphorylation
6.
Theranostics ; 10(5): 2008-2028, 2020.
Article in English | MEDLINE | ID: mdl-32104498

ABSTRACT

CDK4/cyclin D kinase constitutes an attractive pharmacological target for development of anticancer therapeutics, in particular in KRAS-mutant lung cancer patients, who have a poor prognosis and no targeted therapy available yet. Although several ATP-competitive inhibitors of CDK4 have been developed for anticancer therapeutics, they suffer from limited specificity and efficacy. Methods: As an alternative to ATP-competitive inhibitors we have designed a stapled peptide to target the main interface between CDK4 and cyclin D, and have characterized its physico-chemical properties and affinity to bind cyclin D1. Results: We have validated a positive correlation between CDK4/cyclin D level and KRAS mutation in lung cancer patients. The stapled peptide enters cells rapidly and efficiently, and inhibits CDK4 kinase activity and proliferation in lung cancer cells. Its intrapulmonary administration in mice enables its retention in orthotopic lung tumours and complete inhibition of their growth when co-administered with Abemaciclib. Conclusion: The stapled peptide targeting the main interface between CDK4 and cyclin D provides promising therapeutic perspectives for patients with lung cancer.


Subject(s)
Aminopyridines/pharmacology , Benzimidazoles/pharmacology , Cyclin D/metabolism , Cyclin-Dependent Kinase 4/metabolism , Lung Neoplasms/drug therapy , Peptides/pharmacology , Proto-Oncogene Proteins p21(ras)/drug effects , Aminopyridines/administration & dosage , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Benzimidazoles/administration & dosage , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Humans , Lung Neoplasms/genetics , Mice , Mice, Nude , Mutation , Optical Imaging/methods , Peptides/administration & dosage , Peptides/chemistry , Proto-Oncogene Proteins p21(ras)/metabolism
7.
Chembiochem ; 20(4): 605-613, 2019 02 15.
Article in English | MEDLINE | ID: mdl-30548750

ABSTRACT

The p53 tumour suppressor and guardian of the genome undergoes missense mutations that lead to functional inactivation in 50 % of human cancers. These mutations occur mostly in the DNA-binding domain of the protein, and several of these result in conformational changes that lead to amyloid-like protein aggregation. Herein, we describe a fluorescent biosensor that reports on the R248Q mutant of p53 in vitro and in living cells, engineered through conjugation of an environmentally sensitive probe onto a peptide derived from the primary aggregation segment of p53. This biosensor was characterised both in vitro and by means of fluorescence microscopy following facilitated delivery into cultured cells. It is shown that this biosensor preferentially reports on the p53 R248Q mutant in the PC9 lung cancer cell line compared with other lung cancer cell lines harbouring either wild-type or no p53.


Subject(s)
Biosensing Techniques/methods , Fluorescein-5-isothiocyanate/chemistry , Tumor Suppressor Protein p53/genetics , Amino Acid Sequence , Cell Line, Tumor , Humans , Microscopy, Fluorescence , Mutation, Missense , Peptides/chemistry , Peptides/metabolism
8.
Biotechnol J ; 12(8)2017 Aug.
Article in English | MEDLINE | ID: mdl-28430399

ABSTRACT

Cyclin-dependent kinases constitute attractive pharmacological targets for cancer therapeutics, yet inhibitors in clinical trials target the ATP-binding pocket of the CDK and therefore suffer from limited selectivity and emergence of resistance. The more recent development of allosteric inhibitors targeting conformational plasticity of protein kinases offers promising perspectives for therapeutics. In particular tampering with T-loop dynamics of CDK2 kinase would provide a selective means of inhibiting this kinase, by preventing its conformational activation. To this aim we engineered a fluorescent biosensor that specifically reports on conformational changes of CDK2 activation loop and is insensitive to ATP or ATP-competitive inhibitors, which constitutes a highly sensitive probe for identification of selective T-loop modulators. This biosensor was successfully applied to screen a library of small chemical compounds leading to discovery of a family of quinacridine analogs, which potently inhibit cancer cell proliferation, and promote accumulation of cells in S phase and G2. These compounds bind CDK2/ Cyclin A, inhibit its kinase activity, compete with substrate binding, but not with ATP, and dock onto the T-loop of CDK2. The best compound also binds CDK4 and CDK4/Cyclin D1, but not CDK1. The strategy we describe opens new doors for the discovery of a new class of allosteric CDK inhibitors for cancer therapeutics.


Subject(s)
Cell Proliferation/drug effects , Cyclin-Dependent Kinase 2/chemistry , Neoplasms/drug therapy , Quinacrine/administration & dosage , Adenosine Triphosphate/chemistry , Allosteric Regulation/drug effects , Biosensing Techniques , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Humans , Neoplasms/chemistry , Neoplasms/pathology , Protein Conformation/drug effects , Protein Kinase Inhibitors/chemistry , Quinacrine/chemistry , Quinacrine/isolation & purification , Small Molecule Libraries/administration & dosage , Small Molecule Libraries/isolation & purification , Structure-Activity Relationship
9.
Biosens Bioelectron ; 85: 371-380, 2016 Nov 15.
Article in English | MEDLINE | ID: mdl-27203461

ABSTRACT

Melanoma constitutes the most aggressive form of skin cancer, which further metastasizes into a deadly form of cancer. The p16(INK4a)-Cyclin D-CDK4/6-pRb pathway is dysregulated in 90% of melanomas. CDK4/Cyclin D kinase hyperactivation, associated with mutation of CDK4, amplification of Cyclin D or loss of p16(INK4a) leads to increased risk of developing melanoma. This kinase therefore constitutes a key biomarker in melanoma and an emerging pharmacological target, however there are no tools enabling direct detection or quantification of its activity. Here we report on the design and application of a fluorescent peptide biosensor to quantify CDK4 activity in melanoma cell extracts, skin biopsies and melanoma xenografts. This biosensor provides sensitive means of comparing CDK4 activity between different melanoma cell lines and further responds to CDK4 downregulation by siRNA or small-molecule inhibitors. By affording means of monitoring CDK4 hyperactivity consequent to cancer-associated molecular alterations in upstream signaling pathways that converge upon this kinase, this biosensor offers an alternative to immunological identification of melanoma-specific biomarkers, thereby constituting an attractive tool for diagnostic purposes, providing complementary functional information to histological analysis, of particular utility for detection of melanoma onset in precancerous lesions. This is indeed the first fluorescent peptide biosensor which has been successfully implemented to monitor kinase activity in skin samples and melanoma tumour xenografts. Moreover by enabling to monitor response to CDK4 inhibitors, this biosensor constitutes an attractive companion assay to identify compounds of therapeutic relevance for melanoma.


Subject(s)
Biosensing Techniques/methods , Cyclin-Dependent Kinase 4/metabolism , Fluorescent Dyes/metabolism , Melanoma/metabolism , Peptides/metabolism , Skin Neoplasms/metabolism , Skin/pathology , Amino Acid Sequence , Animals , Cell Extracts/chemistry , Cell Line, Tumor , Cyclin-Dependent Kinase 4/analysis , Enzyme Assays/methods , Fluorescent Dyes/chemistry , Melanoma/pathology , Mice , Mice, Nude , Models, Molecular , Peptides/chemistry , Skin/metabolism , Skin Neoplasms/pathology , Spectrometry, Fluorescence/methods
10.
Chembiochem ; 17(8): 737-44, 2016 Apr 15.
Article in English | MEDLINE | ID: mdl-26946188

ABSTRACT

Understanding the intricate steps of protein kinase regulation requires characterization of protein-protein interactions between the catalytic subunit, its regulatory partners and the substrate. Fluorescent probes are useful tools with which to study such interactions and to gain insight into their affinities and specificities. Solvatochromic probes, which display changes in their fluorescence emission in response to changes in the polarity of the medium, are particularly attractive. Here we describe conjugation of a switchable fluorescent dye, TP-2Rho, to peptide and protein derivatives of cyclin-dependent kinase 4 (CDK4) and its application to characterization of the interactions between the catalytic subunit of this kinase, its regulatory partner cyclin D1 and a peptide substrate. We demonstrate the sensitivity of TP-2Rho in relation to of those other dyes used for monitoring peptide-protein and protein-protein interactions. Moreover, we show that TP-Rho-labelled peptides can be introduced into living cells to probe endogenous CDK4/cyclin D.


Subject(s)
Cyclin D/chemistry , Cyclin D/metabolism , Cyclin-Dependent Kinase 4/chemistry , Cyclin-Dependent Kinase 4/metabolism , Fluorescent Dyes/chemistry , Maleimides/chemistry , Thiazolidines/chemistry , Fluorescent Dyes/chemical synthesis , HeLa Cells , Humans , Maleimides/chemical synthesis , Models, Molecular , Molecular Structure , Protein Binding , Thiazolidines/chemical synthesis
11.
Chembiochem ; 16(3): 432-9, 2015 Feb 09.
Article in English | MEDLINE | ID: mdl-25619419

ABSTRACT

Cyclin-dependent kinases (CDKs) control many cellular processes and are considered important therapeutic targets. Large collections of inhibitors targeting CDK active sites have been discovered, but their use in chemical biology or drug development has been often hampered by their general lack of specificity. An alternative approach to develop more specific inhibitors is targeting protein interactions involving CDKs. CKS proteins interact with some CDKs and play important roles in cell division. We discovered two small-molecule inhibitors of CDK-CKS interactions. They bind to CDK2, do not inhibit its enzymatic activity, inhibit the proliferation of tumor cell lines, induce an increase in G1 and/or S-phase cell populations, and cause a decrease in CDK2, cyclin A, and p27(Kip1) levels. These molecules should help decipher the complex contributions of CDK-CKS complexes in the regulation of cell division, and they might present an interesting therapeutic potential.


Subject(s)
CDC2-CDC28 Kinases/metabolism , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Small Molecule Libraries/pharmacology , CDC2-CDC28 Kinases/antagonists & inhibitors , Carrier Proteins/metabolism , Cell Cycle Proteins/metabolism , Cell Division/drug effects , Cyclin A/antagonists & inhibitors , Cyclin A/metabolism , Cyclin-Dependent Kinase 2/metabolism , Dose-Response Relationship, Drug , High-Throughput Screening Assays , Humans , MCF-7 Cells/drug effects , Molecular Docking Simulation , Molecular Structure , Molecular Targeted Therapy , Protein Interaction Maps/drug effects , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism
12.
Cancers (Basel) ; 7(1): 179-237, 2015 Jan 23.
Article in English | MEDLINE | ID: mdl-25625291

ABSTRACT

Cyclin-dependent kinases (CDK/Cyclins) form a family of heterodimeric kinases that play central roles in regulation of cell cycle progression, transcription and other major biological processes including neuronal differentiation and metabolism. Constitutive or deregulated hyperactivity of these kinases due to amplification, overexpression or mutation of cyclins or CDK, contributes to proliferation of cancer cells, and aberrant activity of these kinases has been reported in a wide variety of human cancers. These kinases therefore constitute biomarkers of proliferation and attractive pharmacological targets for development of anticancer therapeutics. The structural features of several of these kinases have been elucidated and their molecular mechanisms of regulation characterized in depth, providing clues for development of drugs and inhibitors to disrupt their function. However, like most other kinases, they constitute a challenging class of therapeutic targets due to their highly conserved structural features and ATP-binding pocket. Notwithstanding, several classes of inhibitors have been discovered from natural sources, and small molecule derivatives have been synthesized through rational, structure-guided approaches or identified in high throughput screens. The larger part of these inhibitors target ATP pockets, but a growing number of peptides targeting protein/protein interfaces are being proposed, and a small number of compounds targeting allosteric sites have been reported.

13.
Chembiochem ; 15(15): 2298-305, 2014 Oct 13.
Article in English | MEDLINE | ID: mdl-25209885

ABSTRACT

Cyclin-dependent kinases (CDKs) play an essential role in the coordination of cell cycle progression and transcriptional regulation; hyperactivation is associated with cancer. However there are few means of measuring their activity in a physiological context or their inhibition in response to therapeutics. To this aim we engineered a modular fluorescent protein biosensor that reports on phosphorylation by CDK/cyclins through real-time changes in fluorescence intensity. This allowed a comparison of enzymatic activity of recombinant kinases, monitoring inhibition by small molecules, and probing endogenous activities in lysates from healthy and cancer cell lines in a sensitive and quantitative fashion. This versatile tool was further implemented to probe the oscillatory activity of these kinases throughout the cell cycle by time-lapse imaging and ratiometric fluorescence quantification, following delivery of a red fluorescent protein fusion mediated by cell-penetrating peptides.


Subject(s)
Biosensing Techniques , Cyclin-Dependent Kinases/metabolism , Cyclins/metabolism , Luminescent Proteins/analysis , Cell Survival , Fluorescence , HeLa Cells , Humans , Luminescent Proteins/chemistry , MCF-7 Cells , Tumor Cells, Cultured
14.
Biotechnol J ; 9(2): 253-65, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24357625

ABSTRACT

High throughput screening assays aim to identify small molecules that interfere with protein function, activity, or conformation, which can serve as effective tools for chemical biology studies of targets involved in physiological processes or pathways of interest or disease models, as well as templates for development of therapeutics in medicinal chemistry. Fluorescent biosensors constitute attractive and powerful tools for drug discovery programs, from high throughput screening assays, to postscreen characterization of hits, optimization of lead compounds, and preclinical evaluation of candidate drugs. They provide a means of screening for inhibitors that selectively target enzymatic activity, conformation, and/or function in vitro. Moreover, fluorescent biosensors constitute useful tools for cell- and image-based, multiplex and multiparametric, high-content screening. Application of fluorescence-based sensors to screen large and complex libraries of compounds in vitro, in cell-based formats or whole organisms requires several levels of optimization to establish robust and reproducible assays. In this review, we describe the different fluorescent biosensor technologies which have been applied to high throughput screens, and discuss the prerequisite criteria underlying their successful application. Special emphasis is placed on protein kinase biosensors, since these enzymes constitute one of the most important classes of therapeutic targets in drug discovery.


Subject(s)
Biosensing Techniques , Fluorescent Dyes , High-Throughput Screening Assays , Protein Kinase Inhibitors , Animals , Humans , Mice
15.
PLoS One ; 6(10): e26555, 2011.
Article in English | MEDLINE | ID: mdl-22028905

ABSTRACT

Cyclin-dependant kinases play a central role in coordinating cell growth and division, and in sustaining proliferation of cancer cells, thereby constituting attractive pharmacological targets. However, there are no direct means of assessing their relative abundance in living cells, current approaches being limited to antigenic and proteomic analysis of fixed cells. In order to probe the relative abundance of these kinases directly in living cells, we have developed a fluorescent peptide biosensor with biligand affinity for CDKs and cyclins in vitro, that retains endogenous CDK/cyclin complexes from cell extracts, and that bears an environmentally-sensitive probe, whose fluorescence increases in a sensitive fashion upon recognition of its targets. CDKSENS was introduced into living cells, through complexation with the cell-penetrating carrier CADY2 and applied to assess the relative abundance of CDK/Cyclins through fluorescence imaging and ratiometric quantification. This peptide biosensor technology affords direct and sensitive readout of CDK/cyclin complex levels, and reports on differences in complex formation when tampering with a single CDK or cyclin. CDKSENS further allows for detection of differences between different healthy and cancer cell lines, thereby enabling to distinguish cells that express high levels of these heterodimeric kinases, from cells that present decreased or defective assemblies. This fluorescent biosensor technology provides information on the overall status of CDK/Cyclin complexes which cannot be obtained through antigenic detection of individual subunits, in a non-invasive fashion which does not require cell fixation or extraction procedures. As such it provides promising perspectives for monitoring the response to therapeutics that affect CDK/Cyclin abundance, for cell-based drug discovery strategies and fluorescence-based cancer diagnostics.


Subject(s)
Biosensing Techniques/methods , Cyclin-Dependent Kinases/metabolism , Fluorescent Dyes/metabolism , Peptides/metabolism , Amino Acid Sequence , Cell Survival , Cyclin-Dependent Kinases/chemistry , Cyclins/chemistry , Cyclins/metabolism , HeLa Cells , Humans , Models, Molecular , Molecular Sequence Data , Protein Conformation , Protein Transport
16.
Biochim Biophys Acta ; 1798(12): 2274-85, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20188697

ABSTRACT

Cell-penetrating peptides (CPPs) constitute a family of peptides with the characteristic ability to cross biological membranes and deliver cargo into the intracellular milieu. Several CPPs have been proposed for delivery of polypeptides and proteins into cells through either of two strategies: covalent or complexed in a non-covalent fashion. Members of the PEP family are primary amphipathic peptides which have been shown to deliver peptides and proteins into a wide variety of cells through formation of non-covalent complexes. CADY is a secondary amphipathic peptide which has been demonstrated to deliver short nucleic acids, in particular siRNA with high efficiency. Here we review the characteristics of the PEP and CADY carriers and describe a novel derivative of CADY termed CADY2, which also presents sequence similarities to Pep1. We have compared Pep1, CADY and CADY2 in their efficiency to interact with and internalize short fluorogenic peptides and proteins into cultured cells, and provide evidence that CADY2 can interact with proteins and peptides and deliver them efficiently into living cells, similar to Pep1, but in contrast to CADY which is unable to deliver any peptide, even short negatively charged peptides. This is the first study to investigate the influence of the cargo on the interactions between PEP and CADY carriers, thereby providing novel insights into the physicochemical parameters underlying interactions and cellular uptake of peptides and proteins by these non-covalent CPPs.


Subject(s)
Cell-Penetrating Peptides/chemistry , Cell-Penetrating Peptides/pharmacology , Cell-Penetrating Peptides/pharmacokinetics , Drug Delivery Systems/methods , Animals , Cell Line , Humans
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