Design of indole- and MCR-based macrocycles as p53-MDM2 antagonists

• Constantinos G. Neochoritis,
• Maryam Kazemi Miraki,
• Eman M. M. Abdelraheem,
• Ewa Surmiak,
• Tryfon Zarganes-Tzitzikas,
• Beata Łabuzek,
• Tad A. Holak and
• Alexander Dömling

Beilstein J. Org. Chem. 2019, 15, 513–520, doi:10.3762/bjoc.15.45

• . The aforementioned artificial macrocycles combine the indole ring, a motif found in many bioactive molecules with the drug-like properties of a non-peptide macrocycle. We hypothesize that these chimeric derivatives of an indole and a macrocycle will offer new potential on specific PPIs and other

Aqueous olefin metathesis: recent developments and applications

• Valerio Sabatino and
• Thomas R. Ward

Beilstein J. Org. Chem. 2019, 15, 445–468, doi:10.3762/bjoc.15.39

• interesting applications in plant biology. Olefin metathesis is also used to cross-link peptide fragments. This technology is known as peptide stapling [92]. Blackwell et al. engineered the first stapled peptide in 1998 by introducing two non-natural amino acids bearing a terminal alkene in a peptide sequence

• (e.g., 105, 106) [93]. The cross-linking of the two amino acids by metathesis results in a more rigid and stabilized alpha helix (products 107 and 108, Scheme 23). Although the reaction cannot be classified as aqueous metathesis (the reaction is carried out in CHCl3 and the peptide remains attached to

• the solid phase), this technology has been exploited to disrupt protein–protein interactions (PPIs) in cancer cells [94][95][96]. Aileron Therapeutics recently launched a stapled peptide platform aiming at developing molecules like ALRN-6924, a stapled peptide that interacts with p53 inhibitors MDMX

Synthesis of C₃-symmetric star-shaped molecules containing α-amino acids and dipeptides via Negishi coupling as a key step

• Sambasivarao Kotha and
• Saidulu Todeti

Beilstein J. Org. Chem. 2019, 15, 371–377, doi:10.3762/bjoc.15.33

• peptide dendrimers. Keywords: amino acids; cyclotrimerization; Negishi coupling; peptide; Introduction Optically active C3-symmetric molecules are valuable synthons to design dendrimers, chiral ligands, polymers, and supramolecules [1][2][3][4]. In this regard, 1,3,5-triarylbenzene derivatives are

• /petroleum ether) to afford the C3-symmetric mono- and dipeptide derivatives 11, 12 and 13, respectively. Peptide derivative 11 Colorless solid; yield 86% (89 mg, starting from 100 mg of 10); Rf = 0.46 (7:3 ethyl acetate/petroleum ether); mp 156–158 °C; [α]D25 +25.07 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ

• , 2928, 1606, 1596, 1434, 783, 505 cm−1. Exemplar C3-symmetric peptide scaffolds reported in the literature. Preparation of compound 7 from L-serine (3). Preparation of the trimerized product 9. Synthesis of compound 11 via Negishi cross-coupling reaction. Synthesis of C3-symmetric trimers 12, 13 and 14

Chemical structure of cichorinotoxin, a cyclic lipodepsipeptide that is produced by Pseudomonas cichorii and causes varnish spots on lettuce

• Hidekazu Komatsu,
• Takashi Shirakawa,
• Takeo Uchiyama and
• Tsutomu Hoshino

Beilstein J. Org. Chem. 2019, 15, 299–309, doi:10.3762/bjoc.15.27

• white solid. Its IR spectrum (KBr tablet, Supporting Information File 1, Figure S1) showed strong and broad absorption bands at 1535 cm−1 and 1660 cm−1, indicating that cichorinotoxin has amide groups and that it is a peptide. In addition, a band at 1740 cm−1 (medium) was also observed, suggesting that

• of the fragment ions in the FABMS spectrum of cichorinotoxin (Figure 1) showed the presence of the following peptide segment: Pro-Ala-Ala-Ala-Val-Ala-dhThr-Ala-Val (Figure 2). As described below, this toxin has a 3-hydroxydecanoic acid moiety as a fatty acid. Furthermore, the amino group at the N

• peptide part is cyclized through an ester linkage between two of the amino acid residues (Thr18 and Val22). Thus, cichorinotoxin is classified as a cyclic lipodepsipeptide. To determine the stereochemistry of the amino acids (D or L), we tried to isolate partial fragments by acid hydrolysis. The toxin was

Synthesis of nonracemic hydroxyglutamic acids

• Dorota G. Piotrowska,
• Iwona E. Głowacka,
• Andrzej E. Wróblewski and
• Liwia Lubowiecka

Beilstein J. Org. Chem. 2019, 15, 236–255, doi:10.3762/bjoc.15.22

• biological activity. Indeed, the interest in 3-hydroxyglutamic acid started many years ago by the discovery of this amino acid in hydrolysates of an antibiotic peptide S-520 [24]. It has been proved recently that it was actually the isomer (2S,3R)-2 and it is a fragment of a cyclohexapeptide [25]. (2R,3S)-2

Synthesis of a tubugi-1-toxin conjugate by a modulizable disulfide linker system with a neuropeptide Y analogue showing selectivity for hY1R-overexpressing tumor cells

• Rainer Kufka,
• Robert Rennert,
• Goran N. Kaluđerović,
• Lutz Weber,
• Wolfgang Richter and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2019, 15, 96–105, doi:10.3762/bjoc.15.11

• Pharmaceuticals GmbH, Leberstr. 20, A-1110 Vienna, Austria 10.3762/bjoc.15.11 Abstract Tubugi-1 is a small cytotoxic peptide with picomolar cytotoxicity. To improve its cancer cell targeting, it was conjugated using a universal, modular disulfide derivative. This allowed conjugation to a neuropeptide-Y (NPY

• )-inspired peptide [K4(C-βA-),F7,L17,P34]-hNPY, acting as NPY Y1 receptor (hY1R)-targeting peptide, to form a tubugi-1–SS–NPY disulfide-linked conjugate. The cytotoxic impacts of the novel tubugi-1–NPY peptide–toxin conjugate, as well as of free tubugi-1, and tubugi-1 bearing the thiol spacer (liberated from

• potency of the liberated tubugi-1 that, however, still bears the thiol spacer (tubugi-1-SH) was restored and up to 10-fold higher compared to the entire peptide–toxin conjugate. The conjugate shows toxic selectivity to tumor cell lines overexpressing the hY1R receptor subtype like, e.g., the hard to treat

Lectins of Mycobacterium tuberculosis – rarely studied proteins

• Katharina Kolbe,
• Sri Kumar Veleti,
• Norbert Reiling and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2019, 15, 1–15, doi:10.3762/bjoc.15.1

• host proteins and cell types, for example the invariant N-acetyl-D-glucosamine or N-acetyl-D-galactosamine residues that attach N- or O-glycans, respectively, to the peptide side chains, the large variety and possible permutations of “capping” residues (for example D-mannopyranosides, D

Cross metathesis-mediated synthesis of hydroxamic acid derivatives

• Shital Kumar Chattopadhyay,
• Subhankar Ghosh and
• Suman Sil

Beilstein J. Org. Chem. 2018, 14, 3070–3075, doi:10.3762/bjoc.14.285

• important demonstration of the protocol is the preparation of the unusual amino acid component of the bioactive cyclic peptide Chap-31. Keywords: α-amino acid; catalysis; cross metathesis; hydroxamates; Introduction Cross-metathesis reactions (CM) have rapidly grown [1][2][3] to be a reliable method for

• ] and the didehydrohydroxamate TSA (2) [24], display useful anticancer properties through inhibition of histone deacetylase enzymes (HDAc) and are used as FDA-approved drugs. Similarly, the cyclic peptide Chap-31 (3) [25] with a terminal hydroxamic acid residue has shown promising anticancer activity

• synthesis of the unusual amino acid component of the important anticancer cyclic peptide compound Chap-31, we attempted the cross-metathesis reaction of N-benzyloxyacryl amide 5 with the homoallylglycine derivative 4k (Table 1, entry 11) and the bis-homoallyl glycine derivative 4l (Table 1, entry 12) [32

Protein–protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

• Laura Carro

Beilstein J. Org. Chem. 2018, 14, 2881–2896, doi:10.3762/bjoc.14.267

• the peptide-binding pocket of the β-clamp, they carried out a fluorescence anisotropy titration screening of the Rockefeller University chemical library containing 30,600 polar organic compounds which led to the discovery of RU7 (9, Figure 3) with an inhibition constant of 10 μM. Pleasingly, it was

• antibacterial effects. In addition to small molecules, peptides have also been investigated as disruptors of protein–protein interactions in the sliding clamp. A structure-based approach, using the natural pentapeptide QL(S/D)LF (8, Figure 3) as a template, led to the identification of the short peptide P6 (16

• , Figure 5) with enhanced affinity for the β-clamp (IC50 = 1.12 μM, measured by surface plasmon resonance). This acetylated peptide was used as a lead and further modified at the second position, where the leucine residue was replaced by a cyclohexyl-L-alanyl group (Cha), and also on the terminal

Synthesis of pyrrolidine-based hamamelitannin analogues as quorum sensing inhibitors in Staphylococcus aureus

• Jakob Bouton,
• Kristof Van Hecke,
• Reuven Rasooly and
• Serge Van Calenbergh

Beilstein J. Org. Chem. 2018, 14, 2822–2828, doi:10.3762/bjoc.14.260

• clinical infections. In S. aureus, virulence is mainly mediated by quorum sensing, a bacterial cell-to-cell communication system based on the secretion of signal molecules [9][10][11]. The natural product hamamelitannin (1) has been identified as a non-peptide analogue of RIP (RNAIII-inhibiting protein

Synthesis of mono-functionalized S-diazocines via intramolecular Baeyer–Mills reactions

• Miriam Schehr,
• Daniel Hugenbusch,
• Tobias Moje,
• Christian Näther and
• Rainer Herges

Beilstein J. Org. Chem. 2018, 14, 2799–2804, doi:10.3762/bjoc.14.257

• functionalization such as cross coupling, peptide coupling or further functionalization. The photoswitchable properties of the S-diazocines 1–5 were investigated using UV–vis and NMR spectroscopic methods. The photostationary states (PSS), half-lives (t1/2) and absorption maxima (λmax) were recorded in acetone and

• precursors for the incorporation in photopharmacophores using cross-coupling, peptide coupling or further functionalization methods such as nucleophilic substitution reaction of the benzyl alcohol 5. The yield determining steps prior to the Baeyer–Mills reaction are the formation of the hydroxylamine with

Novel solid-phase strategy for the synthesis of ligand-targeted fluorescent-labelled chelating peptide conjugates as a theranostic tool for cancer

• Sagnik Sengupta,
• Mena Asha Krishnan,
• Premansh Dudhe,
• Ramesh B. Reddy,
• Bishnubasu Giri,
• Sudeshna Chattopadhyay and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2018, 14, 2665–2679, doi:10.3762/bjoc.14.244

• successfully designed and demonstrated a novel continuous process for assembling targeting ligands, peptidic spacers, fluorescent tags and a chelating core for the attachment of cytotoxic molecules, radiotracers, nanomaterials in a standard Fmoc solid-phase peptide synthesis in high yield and purity. The

• differentially protected Fmoc-Lys-(Tfa)-OH plays a vital role in attaching fluorescent tags while growing the peptide chain in an uninterrupted manner. The methodology is versatile for solid-phase resins that are sensitive to mild and strong acidic conditions when acid-sensitive side chain amino protecting

• tag; Fmoc-Lys-(Tfa)-OH; prostate cancer and ovarian cancer; solid-phase peptide synthesis; Introduction The understanding of cell processes is indispensable to devise new strategies for diagnosis and treatment of cancer and inflammatory diseases through targeted drug delivery techniques [1]. The

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• attachment of a cell-penetrating peptide sequence [58]. One additional class, which did show cellular activity, was based on a catechol scaffold [59]. In analogy to the successful discovery of PqsD inhibitors starting from known FabH-targeting compounds (vide supra), ligands of another enzyme with high

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

• Eszter Lajkó,
• Sarah Spring,
• Rózsa Hegedüs,
• Beáta Biri-Kovács,
• Sven Ingebrandt,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 2495–2509, doi:10.3762/bjoc.14.226

• Kaiserslautern, Amerikastraße 1, 66482 Zweibrücken, Germany Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös Loránd University, Pázmány Péter sétány 1/A, 1117 Budapest, Hungary Eötvös Loránd University, Faculty of Science, Institute of Chemistry, Pázmány Péter sétány 1/A, 1117 Budapest

• , Hungary 10.3762/bjoc.14.226 Abstract Background: Peptide hormone-based targeted tumor therapy is an approved strategy to selectively block the tumor growth and spreading. The gonadotropin-releasing hormone receptors (GnRH-R) overexpressed on different tumors (e.g., melanoma) could be utilized for drug

• approaches to diminish this kind of cytotoxic effects on healthy tissues is the employment of drug delivery systems directed specifically to cancer cells. The chemotherapeutic drug targeting is often based on the receptors for certain peptide hormones that are preferentially expressed by cancer cells. The

Synergistic approach to polycycles through Suzuki–Miyaura cross coupling and metathesis as key steps

• Sambasivarao Kotha,
• Milind Meshram and
• Chandravathi Chakkapalli

Beilstein J. Org. Chem. 2018, 14, 2468–2481, doi:10.3762/bjoc.14.223

• interests include: organic synthesis, green chemistry, development of new synthetic methods for unusual amino acids, peptide modifications, cross-coupling reactions, and metathesis. Currently, he occupies the Pramod Chaudhari Chair Professor in Green Chemistry. Milind P. Meshram was born in Amravati

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• mechanistic considerations are highlighted in the text when appropriate. Keywords: C–H functionalisation; heterocycles; late-stage functionalisation; medicinal chemistry; organic dyes; organic photocatalysts; peptide chemistry; photoredox catalysis; Review 1 Introduction 1.1 Main advantages of

• Peptide-type linkages Medicinal chemists often draw inspiration from nature for the design of their molecules. With the exception of certain natural products, most naturally occurring biologically active molecules contain amides. The formation of the amide functional group is the most utilised reaction in

• structural characteristic of peptides is the disulfide bridge formed by cysteines. This functional group is much more prevalent in peptide medicinal chemistry. Noël et al. have published a protocol for the aerobic oxidation of thiols to disulfides, using Eosin Y photocatalysis and TMEDA (Scheme 3) [43]. The

Synthesis of new p-tert-butylcalix[4]arene-based polyammonium triazolyl amphiphiles and their binding with nucleoside phosphates

• Vladimir A. Burilov,
• Guzaliya A. Fatikhova,
• Mariya N. Dokuchaeva,
• Ramil I. Nugmanov,
• Diana A. Mironova,
• Pavel V. Dorovatovskii,
• Victor N. Khrustalev,
• Svetlana E. Solovieva and
• Igor S. Antipin

Beilstein J. Org. Chem. 2018, 14, 1980–1993, doi:10.3762/bjoc.14.173

• publications have been reported about receptors that more effectively interact with less charged nucleotides. For instance, Kuchelmeister et al. synthesized a receptor with two symmetric peptide arms decorated with guanidinium-based anion binding sites. This receptor showed a stronger binding of AMP in

Artificial bioconjugates with naturally occurring linkages: the use of phosphodiester

• Takao Shoji,
• Hiroki Fukutomi,
• Yohei Okada and
• Kazuhiro Chiba

Beilstein J. Org. Chem. 2018, 14, 1946–1955, doi:10.3762/bjoc.14.169

• bioactivities and/or functions, which has been one of the central topics in the field of chemical biology [16][17][18][19][20][21][22][23][24][25][26]. Since peptide synthesis and oligonucleotide synthesis require different chemistries, such conjugations are typically carried out in the latter stages of the

• linkages that can be formed between native functional groups would be safe alternatives, and are known as natural conjugates such as nucleopeptides and nucleolipids [49]. We have been developing alkyl chain soluble support (ACSS)-assisted liquid-phase methods, specifically for peptide and oligonucleotide

• supported reactants would be unique alternatives that allow the use of unactivated amino acids or nucleosides. In peptide synthesis, activation of the N-terminus is rather rare, except for some recent encouraging examples [62][63][64][65][66][67][68]; however, this is not the case for oligonucleotide

Diazirine-functionalized mannosides for photoaffinity labeling: trouble with FimH

• Femke Beiroth,
• Tomas Koudelka,
• Thorsten Overath,
• Stefan D. Knight,
• Andreas Tholey and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1890–1900, doi:10.3762/bjoc.14.163

• from p-nitrophenyl α-D-mannopyranoside (1), which was first reduced to the corresponding amine 6 [26][27] by catalytic hydrogenation (Scheme 1). HATU-mediated peptide coupling with Boc-protected glycine under basic conditions led to 7. After removal of the Boc protecting group using trifluoroacetic

• acid in water, the resulting crude product was subjected to a subsequent peptide-coupling reaction employing the carboxy-functionalized diazirine 8. Diazirine 8 was prepared in a nine-step synthesis according to the literature [28]. For the synthesis of ligand 4, mannoside 6 was first converted into

• the squaric acid monoester 10 employing squaric acid diester 9. The monoester 10 was reacted with N-Boc-ethylendiamine to obtain the squaric acid diamide 11. Then removal of the Boc protecting group with trifluoroacetic acid followed by peptide coupling with the diazirine 8 led to target molecule 4

A hemicryptophane with a triple-stranded helical structure

• Augustin Long,
• Olivier Perraud,
• Erwann Jeanneau,
• Christophe Aronica,
• Jean-Pierre Dutasta and
• Alexandre Martinez

Beilstein J. Org. Chem. 2018, 14, 1885–1889, doi:10.3762/bjoc.14.162

• parallel peptide chains coil about each other in a triple stranded left-handed helical structure. Its high thermal and mechanical stability results mainly from the numerous hydrogen bonds found in the triple helix framework [2]. Bioinspired structures, based on peptide backbones, have been built, allowing

Defining the hydrophobic interactions that drive competence stimulating peptide (CSP)-ComD binding in Streptococcus pneumoniae

• Bimal Koirala,
• Robert A. Hillman,
• Erin K. Tiwold,
• Michael A. Bertucci and
• Yftah Tal-Gan

Beilstein J. Org. Chem. 2018, 14, 1769–1777, doi:10.3762/bjoc.14.151

• significant attention as a potential antivirulence alternative to traditional antibiotics. Streptococcus pneumoniae, a notorious human pathogen responsible for a variety of acute and chronic infections, utilizes the competence regulon and its associated signaling peptide, the competence stimulating peptide

• (CSP), to acquire antibiotic resistance and establish an infection. In this work, we sought to define the binding pockets within the ComD1 receptor used for binding the hydrophobic side-chain residues in CSP1 through the introduction of highly-conservative point mutations within the peptide

• stimulating peptide (CSP); protein–peptide interactions; quorum sensing; Streptococcus pneumoniae; structure–activity relationships (SAR); Introduction Quorum sensing (QS), a cell-density mechanism utilized by bacteria to assess their population density through the detection of diffusible signal molecules

Synthesis and photophysical studies of a multivalent photoreactive Ru^II-calix[4]arene complex bearing RGD-containing cyclopentapeptides

• Sofia Kajouj,
• Lionel Marcelis,
• Alice Mattiuzzi,
• Adrien Grassin,
• Damien Dufour,
• Pierre Van Antwerpen,
• Didier Boturyn,
• Eric Defrancq,
• Mathieu Surin,
• Julien De Winter,
• Pascal Gerbaux,
• Ivan Jabin and
• Cécile Moucheron

Beilstein J. Org. Chem. 2018, 14, 1758–1768, doi:10.3762/bjoc.14.150

• , once incorporated into targeted cancer cells thanks to the multivalent platform. Keywords: anticancer drug; calixarene; cell targeting; RGD peptide; ruthenium complex; Introduction Long-living luminescent polyazaaromatic ruthenium(II) complexes are intensively studied in a biological context, in

• polyarginine [34][35][36][37]. The tethering of a photoreactive RuII complex on the transactivating transcriptional activator (TAT) peptide was also reported and it was shown that the corresponding RuII conjugate could be internalized inside HeLa cells without any modification of the photochemical properties

• anchoring i) of the photoreactive [Ru(TAP)2phen]2+ complex on the calix[4]arene small rim through a peptide-type coupling and ii) of the four c-[RGDfK] moieties on the opposite rim through a copper-catalyzed azide–alkyne cycloaddition (CuAAC) [66][67][68] (Figure 1). It was thus necessary to block the calix

Natural and redesigned wasp venom peptides with selective antitumoral activity

• Marcelo D. T. Torres,
• Gislaine P. Andrade,
• Roseli H. Sato,
• Cibele N. Pedron,
• Tania M. Manieri,
• Giselle Cerchiaro,
• Anderson O. Ribeiro,
• Cesar de la Fuente-Nunez and
• Vani X. Oliveira Jr.

Beilstein J. Org. Chem. 2018, 14, 1693–1703, doi:10.3762/bjoc.14.144

• show that both a natural antimicrobial peptide (AMP) derived from wasp venom (decoralin, Dec-NH2), and its synthetic variants generated via peptide design, display potent activity against cancer cells. We tested the derivatives at increasing doses and observed anticancer activity at concentrations as

• low as 12.5 μmol L−1 for the selective targeting of MCF-7 breast cancer cells. Flow cytometry assays further revealed that treatment with wild-type (WT) peptide Dec-NH2 led to necrosis of MCF-7 cells. Additional atomic force microscopy (AFM) measurements indicated that the roughness of cancer cell

• membranes increased significantly when treated with lead peptides compared to controls. Biophysical features such as helicity, hydrophobicity, and net positive charge were identified to play an important role in the anticancer activity of the peptides. Indeed, abrupt changes in peptide hydrophobicity and

Drug targeting to decrease cardiotoxicity – determination of the cytotoxic effect of GnRH-based conjugates containing doxorubicin, daunorubicin and methotrexate on human cardiomyocytes and endothelial cells

• Livia Polgár,
• Eszter Lajkó,
• Pál Soós,
• Orsolya Láng,
• Marilena Manea,
• Béla Merkely,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 1583–1594, doi:10.3762/bjoc.14.136

• , Nagyvárad tér 4., Budapest, 1089, Hungary University of Konstanz, Department of Chemistry and Zukunftskolleg, Universitätsstrasse 10, 78467 Konstanz, Germany Eötvös Loránd University, Faculty of Science, Institute of Chemistry, Pázmány P. stny 1/A Budapest, 1117, Hungary MTA-ELTE Research Group of Peptide

• : cardiotoxicity; drug targeting; GnRH-conjugates; HCM; HUVEC; impedimetry; Introduction Gonadotropin-releasing hormone (GnRH) is a peptide hormone secreted by the hypothalamus, which stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. Thus, it represents

• ]. These side effects can limit the applicability of these chemotherapeutic drugs. The conjugation of doxorubicin and daunorubicin to a GnRH-III-based targeting peptide could lead to decreased cardiotoxic effect through the more specific drug targeting. Drug delivery systems containing doxorubicin

Design and biological characterization of novel cell-penetrating peptides preferentially targeting cell nuclei and subnuclear regions

• Anja Gronewold,
• Mareike Horn and
• Ines Neundorf

Beilstein J. Org. Chem. 2018, 14, 1378–1388, doi:10.3762/bjoc.14.116

• ) with selective suborganelle-targeting properties. The nuclear localization sequence N50, as well as the nucleoli-targeting sequence NrTP, respectively, were fused to a shortened version of the cell-penetrating peptide sC18. We examined cellular uptake, subcellular fate and cytotoxicity of these novel

• excluded. However, initial drug delivery studies demonstrated the high versatility of these new peptides as efficient transport vectors targeting specifically nuclei and nucleoli. In future, they could be further explored as parts of newly created peptide–drug conjugates. Keywords: anticancer drugs; cell

• direct penetration. The latter is described for those cases, where only small cargos are attached to the CPP [11]. We have designed a cell-penetrating peptide sequence, namely sC18, which we efficiently used in previous studies as drug transporter [12][13][14][15][16][17]. sC18 is composed of the last 16