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Investigation of the Stereochemical-Dependent DNA and RNA Binding of Arginine-Based Nucleopeptides

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Investigation of the Stereochemical-Dependent DNA and RNA Binding of Arginine-Based Nucleopeptides S S symmetry Article Investigation of the Stereochemical-Dependent DNA and RNA Binding of Arginine-Based Nucleopeptides Stefano Tomassi 1 , Francisco Franco Montalban 2 , Rosita Russo 1, Ettore Novellino 3, Anna Messere 1,* and Salvatore Di Maro 1,* 1 DISTABiF, Università degli Studi della Campania “Luigi Vanvitelli”, via A. Vivaldi 43, 81100 Caserta, Italy; [email protected] (S.T.); [email protected] (R.R.) 2 Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, “Campus de Cartuja”, Granada University, 18071 Granada, Spain; ff[email protected] 3 Dipartimento di Farmacia, Università degli Studi di Napoli “Federico II”, via D. Montesano 49, 80131 Napoli, Italy; [email protected] * Correspondence: [email protected] (A.M.); [email protected] (S.D.M.) Received: 28 March 2019; Accepted: 17 April 2019; Published: 19 April 2019 Abstract: Nucleopeptides represent an intriguing class of nucleic acid analogues, in which nucleobases are placed in a peptide structure. The incorporation of D- and/or L-amino acids in nucleopeptide molecules allows the investigation of the role of backbone stereochemistry in determining the formation of DNA and RNA hybrids. Circular Dichroism (CD) spectroscopic studies indicated the nucleopeptide as having fully l-backbone configuration-formed stable hybrid complexes with RNA molecules. Molecular Dynamics (MD) simulations suggested a potential structure of the complex resulting from the interaction between the l-nucleopeptide and RNA strand. From this study, both the backbone (ionics and H-bonds) and nucleobases (pairing and π-stacking) of the chiral nucleopeptide appeared to be involved in the hybrid complex formation, highlighting the key role of the backbone stereochemistry in the formation of the nucleopeptide/RNA complexes. Keywords: nucleic acid; nucleopeptides; backbone stereochemistry; solid-phase synthesis; molecular dynamic simulation 1. Introduction Nucleic acid–protein interactions are crucial in numerous cell functions, including transcription, translation and RNA maturation, which in turn modulate numerous physio-pathological processes [1,2]. They regulate genetic information transfer by proper interaction between protein binding domains and specific regions of nucleic acids [3–6]. The formation of highly stable and specific complexes depends on the strict recognition rules regulating the nucleobase association for nucleic acids and on a wide array of aminoacid–nucleobase interactions, including hydrophobic, ionic and hydrogen bonds for the nucleic acid–protein complexes. In the present day, the use of nucleobases constituting DNA and RNA aptamers is a well-established approach to interfere with both nucleic acid and protein targets for the diagnosis and the therapeutic treatment of numerous diseases, including cancer, inflammation and infections [7]. In spite of their great potential, the full capitalization of these chemotypes as therapeutics is still limited by several drawbacks, such as low chemical variability, binding affinity and metabolic stability. In this regard, DNA aptamers containing pyrimidine bases endowed with amino acid residues (SOMAmer) [8,9] represent an enhancement in chemical diversity providing wide application as diagnostic and therapeutic tools. Alternatively, nucleobases have been added to peptides as recognition units by employing nucleobase amino acids (NBA) [10–15]. To date, no study has been reported describing the use of NBA as elements to improve the selective protein recognition of target Symmetry 2019, 11, 567; doi:10.3390/sym11040567 www.mdpi.com/journal/symmetry Symmetry 2019, 11 FOR PEER REVIEW 2 Alternatively, nucleobases have been added to peptides as recognition units by employing Symmetry 2019, 11, 567 2 of 16 nucleobase amino acids (NBA) [10–15]. To date, no study has been reported describing the use of NBA as elements to improve the selective protein recognition of target nucleic acids. Nevertheless, this basic concept hasnucleic been acids.proposed Nevertheless, in several thisstudies basic [1 concept6] involving has beenpeptide proposed-based molecules, in several studiesin [16] involving order to make novelpeptide-based compounds that molecules, bind DNA in orderand RNA to make specifically, novel compounds such as Peptide that bindNucleic DNA Acid and RNA specifically, (PNA) [17–21]. PNAssuch are as nucleic Peptide acid Nucleic analogues Acid first (PNA) described [17–21]. by PNAs Nielsen are and nucleic coworkers, acid analogues which first described by have been largely appliedNielsen for and chemical coworkers, biology which investigations. have been largely They are applied able to for efficient chemically mimic biology DNA investigations. They are molecules through ablea pseudopeptide to efficiently backbone mimic DNA formed molecules by achiral through N-(2 a-aminoethyl) pseudopeptide glycine backbone (aeg) formed by achiral moieties bearing nucleobasesN-(2-aminoethyl) linked glycinevia a methylene (aeg) moieties carbonyl bearing bridge. nucleobases Although linked PNAs via selectively a methylene carbonyl bridge. recognize DNA andAlthough RNA sequences PNAs selectivelyaffording very recognize stable hybrids, DNA and the RNA absence sequences of chiral aff centersording in very its stable hybrids, the backbone hampers absencethe folding of chiralin specific centers conformations, in its backbone reducing hampers its ability the folding to discriminate in specific highly conformations, reducing structured DNA andits abilityRNA tomole discriminatecules. Additionally, highly structured PNAs DNAexhibit and numerous RNA molecules. disadvantages, Additionally, PNAs exhibit including low solubilitynumerous in an disadvantages, aqueous medium including, ambiguous low solubility directional in anselectivity aqueous of medium, DNA/RNA ambiguous directional binding, and low cellselectivity permeability of DNA. /RNA binding, and low cell permeability. To address some of Tothe address above-mentioned some of the issues, above-mentioned several modifications issues, several have modificationsbeen performed have on been performed on the original PNA structurethe original [22– PNA24]. For structure instance, [22 –the24]. incorporation For instance, of the N incorporation-(2-aminoethyl) of-D N-(2-aminoethyl)-D-Lysine-Lysine residues led to the synthesisresidues ledof cationic to the synthesis PNAs, which of cationic combined PNAs, the which nucleic combined acid recognition the nucleic ability acid of recognition ability of PNA with the cell permeabilityPNA with the of cellcationic permeability cell penetrating of cationic peptides cell penetrating (CPP). These peptides new PNA (CPP). variants These new PNA variants displayed advantagesdisplayed in terms advantages of solubility in termsand bindin of solubilityg to DNA and [23 binding,24]. Crystallographic to DNA [23,24 ].studies Crystallographic studies demonstrated that demonstratedthe backbone that chirality the backbone could chiralityconformationally could conformationally modulate the modulate PNA helical the PNA helical direction, direction, thereby enhancingthereby enhancing the recognition the recognition specificity specificity of the target of the [25 target–27]. [In25 –li27ne]. with In line the with resul thets results achieved by achieved by studyingstudying CPPs, CPPs,the presence the presence of the ofpositive the positive charge charge of Lys of side Lys-chain side-chainss enhanced enhanced their their solubility and solubility and especiallyespecially their theircell permeability cell permeability,, most mostlikely likely through through an endosomal an endosomal pathway pathway or direct or direct cell membrane cell membrane penetrationpenetration [28]. [28 Similarly,]. Similarly, new new classes classes of of chiral chiral PNAs PNAs (α, (α ,and and ɣ--GPNA)GPNA) havehave beenbeen recently designed by recently designed bymerging merging the the recognition recognition ability ability of PNA of PNA with thewith uptake the uptake features features of cationic of guanidiniumcationic groups [29,30]. guanidinium groupsThese [29, studies30]. These showed studies that showed GPNAs that with GPNAsα-d and /withor - lα-backbone-D and/or configuration ɣ-L-backbone exhibited improved configuration exhibitedcellular improved uptake, cellular increased uptake, binding increased affinity binding for DNA affinity and RNA,for DNA and and enhanced RNA, and thermal stability of the enhanced thermal stabilityresulting of hybrids.the resulting These hybrids. favorable These properties favorable were properties ascribable were to ascribable the conformational to the preorganization conformational preorganizationof chiral PNAs of andchiral the PNAs electrostatic and the interactions electrostatic between interactions cationic between guanidine cationic and phosphate groups. guanidine and phosphateIn particular, groups. they demonstrated In particular that, thethey backbone demonstrated stereochemistry that the contributed backbone more with respect to stereochemistry contributedthe electrostatic more with forces respect in stabilizing to the theelectrostatic hybrid duplex. forces in stabilizing the hybrid duplex. In this regard, nucleopeptides represent alternative chemotypes in which nucleobases are combined In this regard,with nucleopeptides a peptide structure represent [31– 33alternative]. This fascinating chemotypes class in of moleculeswhich nucleobases are characterized are by the presence combined with a peptideof amino structure acids-bearing [31–33].
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