Structural polymorphism of DNA has constantly been evolving from the time of illustration of the double helical model of DNA by Watson and Crick. A variety of non-canonical DNA structures have constantly been documented across the globe. DNA attracted worldwide attention as a carrier of genetic information. In addition to the classical Watson–Crick duplex, DNA can actually adopt diverse structures during its active participation in cellular processes like replication, transcription, recombination and repair. Structures like hairpin, cruciform, triplex, G-triplex, quadruplex, i-motif and other alternative non-canonical DNA structures have been studied at length and have also shown their in vivo occurrence. This review mainly focuses on non-canonical structures adopted by DNA oligonucleotides which have certain prerequisites for their formation in terms of sequence, its length, number and orientation of strands along with varied solution conditions. This conformational polymorphism of DNA might be the basis of different functional properties of a specific set of DNA sequences, further giving some insights for various extremely complicated biological phenomena. Many of these structures have already shown their linkages with diseases like cancer and genetic disorders, hence making them an extremely striking target for structure-specific drug designing and therapeutic applications.

A gradual dementia, which leads to the loss of memory and intellectual abilities, is the main characteristics of Alzheimer’s disease. Amyloid-β (Aβ) plaques are the main components that accumulate and form clumps in the brains of people suffering from Alzheimer’s disease. Apolipoprotein E (APOE), an amyloid-binding protein is considered as one of the main genetic risk factor of the late-onset Alzheimer’s disease. Different isoforms of APOE gene named APOE2, APOE3, and APOE4 are known to exist, which differ from each other at certain positions involving single-nucleotide polymorphisms (SNPs). Out of these isoforms, APOE4 increases the risk of developing late-onset Alzheimer’s disease, whereas APOE3 is the most common among the general population. APOE4 differs from the common APOE3 by only one nucleotide at position +2985 (T to C), which results in immense alteration in the structure and function of the APOE gene. A combination of gel electrophoresis (polyacrylamide gel electrophoresis, PAGE), circular dichroism (CD), CD melting, thermal difference spectra and UV-thermal denaturation (TM) techniques was used to investigate the structural polymorphism associated with T → C single-nucleotide polymorphism (SNP) at the GC-rich sequence (d-TGGAGGACGTGTGCGGCCGCCT; APOE22T). Herein, we report that APOE22T DNA sequence switches between hairpin to antiparallel quadruplex from low to high oligomer concentration. On the contrary, its C-counterpart (APOE22C) forms hairpin as well as intermolecular antiparallel duplex structure. This structural change may possibly contribute to the protein recognition pattern, which, in turn, might control the APOE gene expression.

An exceptional property of auto-folding into a range of intra- as well as intermolecular quadruplexes by guanine-rich oligomers (GROs) of promoters, telomeres and various other genomic locations is still one of the most attractive areas of research at present times. The main reason for this attention is due to their established in vivo existence and biological relevance. Herein, the structural status of a 20-nt long G-rich sequence with two G5 stretches (SG20) is investigated using various biophysical and biochemical techniques. Bioinformatics analysis suggested the presence of a 17-nt stretch of this SG20 sequence in the intronic region of human SYTX (Synaptotagmin 10) gene. The SYTX gene helps in sensing out the Ca ion, causing its intake in the pre-synaptic neuron. A range of various topologies like bimolecular, tetramolecular and guanine-wires (nano-wires) was exhibited by the studied sequence, as a function of cations (Na /K ) concentration. UV-thermal denaturation, gel electrophoresis, and circular dichroism (CD) spectroscopy showed correlations and established a cation-dependent structural switch. The G-wire formation, in the presence of K , may further be explored for its possible relevance in nano-biotechnological applications.

2‐Hydroxy‐naphthaldehyde based heterocyclic Schiff base derivatives (1 a‐1 h) were prepared and characterized by multi‐spectroscopic techniques and elemental analysis. Antibacterial activity of all the compounds was tested against Streptococcus pneumoniae, Enterococcus faecalis, Pseudomonas aeruginosa, Salmonella enterica, Klebsiella pneumoniae and Escherichia coli bacterial strains. The antifungal potential of the synthesized compounds was also tested against three Candida strains (Candida albicans, Candida glabrata and Candida tropicalis). In the antibacterial activity, the compounds showed high MIC values and thus found less potent against all the tested bacterial strains. Interestingly, compounds 1 b and 1 c exhibited significant activity with MIC 125 μg/ml against all the tested fungal strains. Hemolytic assay against human RBCs revealed that compounds 1 b and 1 c showed less toxicity than the standard drug fluconazole at each tested concentration (25‐1000 μg/ml). In growth kinetics studies, compounds 1 b and 1 c significantly inhibited the growth of Candida cells at 2MIC and MIC concentrations. The interaction ability of lead compounds (1 b and 1 c) with Ct–DNA was carried out by absorption, fluorescence, hydrodynamic, cyclic voltammetery measurements and circular dichroism. Results suggested that compound 1 b and 1 c bind to Ct–DNA via an intercalative mode supported by molecular docking studies. The antioxidant potential of heterocyclic derivatives 1 b and 1 c was estimated by DPPH free radical and hydrogen peroxide assay which confirm that compounds exhibited significant antioxidant activity.

Structural polymorphism is an extremely significant phenomenon of nucleic acids, in which DNA and RNA oligonucleotide sequences are able to adapt various canonical, alternative and multistranded structures. These alternative forms of DNA and RNA have an enormous potential of participating in various cellular processes by recognizing ligands such as proteins, drugs and metal ions in a sequence and structure-specific manner. Such DNA-ligand interactions prove to be highly beneficial when exploited for therapeutic purposes. Many of these DNA/ RNA structures recognizing drugs have already proved their potential as anticancer, antibacterial, anthelmintic and antiviral properties. Over the last 2-3 decades, many mechanisms of DNA-drug interactions have been documented, but still many other new mechanisms are being explored. Designing new drugs with improved efficacy and specificity is of prime concern for all researchers which not only deals with the experiments related to synthesizing drugs, but also takes care of searching novel routes or agents for administration or delivery of these therapeutic agents by increasing their nuclear and cellular uptake. This review aims at explaining the structural polymorphs/ multistranded DNA structures and their interactions with pharmaceutical drugs in a structure-specific manner, along with their modes of interactions and biological relevance. This detailed overview of multistranded DNA structures and interacting drugs might further facilitate our understanding about molecular targets and drug development in a more precise manner for the larger benefit of mankind.

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