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Proceedings of the National Academy of... Dec 1987We present a comparative study of calorimetrically derived thermodynamic profiles for the binding of a series of drugs with selected DNA host duplexes. We use these data...
We present a comparative study of calorimetrically derived thermodynamic profiles for the binding of a series of drugs with selected DNA host duplexes. We use these data to demonstrate that comparisons between complete thermodynamic profiles (delta G zero, delta H zero, delta S zero, delta Cp) are required before drug binding can be used as a probe of DNA conformation, since enthalpy-entropy compensations can cause two drug-DNA binding events to exhibit similar binding free energies (delta G zero) despite being driven by entirely different thermodynamic forces (delta H zero, delta S zero). In this work, we employ a combination of spectroscopic and calorimetric techniques to characterize thermodynamically the DNA binding of netropsin and distamycin (two minor groove-directed ligands), ethidium (an intercalator), and daunomycin (a combined intercalator/groove binder). Our free energy data (delta G zero) show that each drug exhibits similar binding affinities at 25 degrees C for the alternating copolymer duplex poly[d(A-T)].poly[d(A-T)] and for the homopolymer duplex poly(dA).poly(dT). However, our calorimetric measurements reveal that the nature of the thermodynamic forces (delta H zero, delta S zero) that drive drug binding to these two host duplexes at 25 degrees C are entirely different, despite similar binding free energies (delta G zero) and similar salt dependencies (lnK/ln[Na+]). Specifically, the 25 degrees C binding of all four drugs to the alternating copolymer poly[d(A-T)].poly[d(A-T)] is overwhelmingly enthalpy driven, whereas the corresponding binding of each drug to the homopolymer duplex poly(dA).poly(dT) is overwhelmingly entropy driven. Thus, the similar binding free energies (delta G zero) we measure for complexation of each drug with poly[d(A-T)].poly[d(A-T)] and poly(dA).poly(dT) result from compensating changes in the enthalpy and entropy terms. Comparison with the thermodynamic profiles for the complexation of these drug molecules to other DNA host duplexes at 25 degrees C reveals that the binding of each is strongly enthalpy driven, except when the poly(dA).poly(dT) homopolymer serves as the host duplex. This comparison allows us to conclude that poly[d(A-T)].poly[d(A-T)] behaves thermodynamically as the more "normal" host duplex toward drug binding, whereas the entropy-driven binding to the poly(dA).poly(dT) duplex represents "aberrant" behavior. Furthermore, since each of the four drugs exhibits different modes of DNA binding, we conclude that the observed entropy-driven behavior for binding to poly(dA).poly(dT) reflects an intrinsic property of the homopolymer duplex that is perturbed in a common manner upon ligation rather than a common property of all four binding ligands. To rationalize the large positive entropy changes that drive drug complexation with poly(dA).poly(dT) duplex, we propose a model that emphasizes binding-induced perturbations of the more highly hydrated, altered B conformation of the homopolymer. Our results suggest that an aberrant thermodynamic binding profile may reflect an unusual DNA conformation in the host duplex. However, before such a conclusion can be reached, complete thermodynamic binding profiles must be examined, since enthalpy-entropy compensations can cause two binding events to exhibit similar binding constants even when they are driven by very different thermodynamic forces.
Topics: Calorimetry; DNA; DNA Damage; Daunorubicin; Distamycins; Ethidium; Guanidines; Intercalating Agents; Netropsin; Nucleic Acid Conformation; Poly dA-dT; Pyrroles; Salts; Thermodynamics
PubMed: 2827160
DOI: 10.1073/pnas.84.24.8922 -
Biochimica Et Biophysica Acta Jul 2002Cellular DNA is not a uniform target for DNA-reactive drugs. At the nucleotide level, drugs recognize and bind short motifs of a few base pairs. The location of drug... (Review)
Review
Cellular DNA is not a uniform target for DNA-reactive drugs. At the nucleotide level, drugs recognize and bind short motifs of a few base pairs. The location of drug adducts at the genomic level depends on how these short motifs are distributed in larger domains. This aspect, referred to as region specificity, may be critical for the biological outcome of drug action. Recent studies demonstrated that certain minor groove binding (MGB) drugs, such as bizelesin, produce region-specific lesions in cellular DNA. Bizelesin binds mainly T(A/T)(4)A sites, which are on average scarce, but occasionally cluster in distinct minisatellite regions (200-1000 bp of approximately 85-100% AT), herein referred to as AT islands. Bizelesin-targeted AT islands are likely to function as strong matrix attachment regions (MARs), domains that organize DNA loops on the nuclear matrix. Distortion of MAR-like AT islands may be a basis for the observed inhibition of new replicon initiation and the extreme lethality of bizelesin adducts (<10 adducts/cell for cell growth inhibition). Hence, long AT-islands represent a novel class of critical targets for anticancer drugs. The AT island paradigm illustrates the potential of the concept of regional targeting as an essential component of the rational design of new sequence-specific DNA-reactive drugs.
Topics: Antineoplastic Agents; Base Sequence; Benzofurans; Binding Sites; Cyclohexanecarboxylic Acids; Cyclohexenes; DNA Damage; DNA, Neoplasm; Distamycins; Drug Design; Duocarmycins; Genome, Human; Humans; Indoles; Nitrogen Mustard Compounds; Tandem Repeat Sequences; Tumor Cells, Cultured; Urea
PubMed: 12084472
DOI: 10.1016/s0925-4439(02)00093-5 -
Nucleic Acids Research Jun 2018The structural differences among different G-quadruplexes provide an opportunity for site-specific targeting of a particular G-quadruplex structure. However, majority of...
The structural differences among different G-quadruplexes provide an opportunity for site-specific targeting of a particular G-quadruplex structure. However, majority of G-quadruplex ligands described thus far show little selectivity among different G-quadruplexes. In this work, we delineate the design and synthesis of a crescent-shaped thiazole peptide that preferentially stabilizes c-MYC quadruplex over other promoter G-quadruplexes and inhibits c-MYC oncogene expression. Biophysical analysis such as Förster resonance energy transfer (FRET) melting and fluorescence spectroscopy show that the thiazole peptide TH3 can selectively interact with the c-MYC G-quadruplex over other investigated G-quadruplexes and duplex DNA. NMR spectroscopy reveals that peptide TH3 binds to the terminal G-quartets and capping regions present in the 5'- and 3'-ends of c-MYC G-quadruplex with a 2:1 stoichiometry; whereas structurally related distamycin A is reported to interact with quadruplex structures via groove binding and end stacking modes with 4:1 stoichiometry. Importantly, qRT-PCR, western blot and dual luciferase reporter assay show that TH3 downregulates c-MYC expression by stabilizing the c-MYC G-quadruplex in cancer cells. Moreover, TH3 localizes within the nucleus of cancer cells and exhibits antiproliferative activities by inducing S phase cell cycle arrest and apoptosis.
Topics: A549 Cells; Apoptosis; Cell Line, Tumor; Cell Proliferation; Distamycins; Down-Regulation; G-Quadruplexes; Gene Expression; HeLa Cells; Humans; Models, Molecular; Neoplasms; Peptides; Proto-Oncogene Proteins c-myc; S Phase Cell Cycle Checkpoints; Structure-Activity Relationship; Thiazoles
PubMed: 29762718
DOI: 10.1093/nar/gky385 -
Proceedings of the National Academy of... Mar 1993In an effort to further extend the number of targets for development of antiretroviral agents, we have used an in vitro integrase assay to investigate a variety of... (Comparative Study)
Comparative Study
In an effort to further extend the number of targets for development of antiretroviral agents, we have used an in vitro integrase assay to investigate a variety of chemicals, including topoisomerase inhibitors, antimalarial agents, DNA binders, naphthoquinones, the flavone quercetin, and caffeic acid phenethyl ester as potential human immunodeficiency virus type 1 integrase inhibitors. Our results show that although several topoisomerase inhibitors--including doxorubicin, mitoxantrone, ellipticines, and quercetin--are potent integrase inhibitors, other topoisomerase inhibitors--such as amsacrine, etoposide, teniposide, and camptothecin--are inactive. Other intercalators, such as chloroquine and the bifunctional intercalator ditercalinium, are also active. However, DNA binding does not correlate closely with integrase inhibition. The intercalator 9-aminoacridine and the polyamine DNA minor-groove binders spermine, spermidine, and distamycin have no effect, whereas the non-DNA binders primaquine, 5,8-dihydroxy-1,4-naphthoquinone, and caffeic acid phenethyl ester inhibit the integrase. Caffeic acid phenethyl ester was the only compound that inhibited the integration step to a substantially greater degree than the initial cleavage step of the enzyme. A model of 5,8-dihydroxy-1,4-naphthoquinone interaction with the zinc finger region of the retroviral integrase protein is proposed.
Topics: Antibiotics, Antineoplastic; Antiviral Agents; Base Sequence; DNA Nucleotidyltransferases; Enzyme Inhibitors; HIV-1; Integrases; Kinetics; Molecular Sequence Data; Naphthoquinones; Oligodeoxyribonucleotides; Recombinant Proteins; Structure-Activity Relationship; Substrate Specificity
PubMed: 8460151
DOI: 10.1073/pnas.90.6.2399 -
European Journal of Medicinal Chemistry Aug 2017This study details the synthesis and biological evaluation of a collection of 19 structurally related Minor Groove Binders (MGBs), derived from the natural product...
This study details the synthesis and biological evaluation of a collection of 19 structurally related Minor Groove Binders (MGBs), derived from the natural product distamycin, which were designed to probe antifungal and antimycobacterial activity. From this initial set, we report several MGBs that are worth more detailed investigation and optimisation. MGB-4, MGB-317 and MGB-325 have promising MICs of 2, 4 and 0.25 μg/mL, respectively, against the fungus C. neoformans.MGB-353 and MGB-354 have MICs of 3.1 μM against the mycobacterium M. tuberculosis. The selectivity and activity of these compounds is related to their physicochemical properties and the cell wall/membrane characteristics of the infective agents.
Topics: Anti-Bacterial Agents; Antifungal Agents; Biological Products; Cryptococcus neoformans; Distamycins; Dose-Response Relationship, Drug; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Structure-Activity Relationship
PubMed: 28544982
DOI: 10.1016/j.ejmech.2017.05.039 -
In Silico Pharmacology 2021Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome coronavirus (MERS-CoV) and the novel SARS-CoV-2 evade the host innate...
UNLABELLED
Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome coronavirus (MERS-CoV) and the novel SARS-CoV-2 evade the host innate immunity, and subsequently the adaptive immune response, employing one protease called Papain-like protease (PLpro). The PLpro and the 3CL main protease are responsible for the cleavage of the polyproteins encoded by the + sense RNA genome of the virus to produce several non-structured proteins (NSPs). However, the PLpro also performs deubiquitination and deISGylation of host proteins and signaling molecules, and thus antagonize the host innate immune response, since ubiquitination and ISGylation are critical processes which invoke host's antiviral immune responses. Thus, to maintain host antiviral defense, inhibition of the PLpro is the primary therapeutic strategy. Furthermore, inhibition of the enzyme prevents replication of the virus. The present study employs molecular modeling approaches to determine potential of different approved and repurposed drugs and other compounds as inhibitors of the SARS-CoV-2 PLpro. The results of the study demonstrated that drugs like Stallimycin, and known protease inhibitors including Telaprevir, Grazoprevir and Boceprevir, were highly potent in inhibiting the enzyme. In addition, several plant-derived polyphenols, including Corylifol A and Kazinol J, were found to be potent inhibitors. Based on the findings, we suggest that clinical trials be initiated with these inhibitors. So far, PLpro inhibition has been given less attention as a strategy to contain COVID-19 pandemic, and thus the present study is of high significance and has therapeutic implications in containing the pandemic.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s40203-021-00085-y.
PubMed: 33842190
DOI: 10.1007/s40203-021-00085-y -
Progress in Biophysics and Molecular... 1986
Review
Nonintercalating DNA-binding ligands: specificity of the interaction and their use as tools in biophysical, biochemical and biological investigations of the genetic material.
Topics: Aminoglycosides; Animals; Anthramycin; Antibiotics, Antineoplastic; Base Sequence; Binding Sites; Bisbenzimidazole; Cattle; Centrifugation, Density Gradient; Chemical Phenomena; Chemistry, Physical; Chromosomes; Circular Dichroism; DNA; DNA, Superhelical; Diminazene; Distamycins; Drug Interactions; Duocarmycins; Indoles; Leucomycins; Ligands; Magnetic Resonance Spectroscopy; Mathematics; Models, Molecular; Netropsin; Plicamycin; Protein Conformation; Pyridinium Compounds; RNA; Spectrophotometry, Ultraviolet; Staining and Labeling; Thermodynamics
PubMed: 2422697
DOI: 10.1016/0079-6107(86)90005-2 -
Communicative & Integrative Biology May 2011We have recently reported the isolation and characterization of Plasmodium falciparum Dbp5/DDX19 homolog PfD66 and the results indicate that it contains ATP-dependent...
We have recently reported the isolation and characterization of Plasmodium falciparum Dbp5/DDX19 homolog PfD66 and the results indicate that it contains ATP-dependent bipolar DNA and RNA unwinding activity, intrinsic nucleic acid-dependent ATPase and RNA-binding activities. In the present study we report the effect of a number of compounds such as actinomycin D, aphidicolin, camptothecin, cyclophosphamide, 4',6'-di-amidino-2-phenylindole (DAPI), daunorubicin, distamycin, ethidium bromide, ellipticine, genistein, mitoxantrone, nalidixic acid, netropsin, nogalamycin, novobiocin and VP-16 on the DNA unwinding and ATPase activities of PfD66. The results indicate that DAPI, ethidium bromide, netropsin and nogalamycin efficiently inhibited the helicase and ATPase activities of PfD66. These studies will make an important contribution in understanding the mechanism of DNA unwinding by Plasmodium falciparum helicase PfD66.
PubMed: 21980563
DOI: 10.4161/cib.4.3.14778 -
PloS One 2013The condensed structure of chromatin limits access of cellular machinery towards template DNA. This in turn represses essential processes like transcription,...
The condensed structure of chromatin limits access of cellular machinery towards template DNA. This in turn represses essential processes like transcription, replication, repair and recombination. The repression is alleviated by a variety of energy dependent processes, collectively known as "chromatin remodeling". In a eukaryotic cell, a fine balance between condensed and de-condensed states of chromatin helps to maintain an optimum level of gene expression. DNA binding small molecules have the potential to perturb such equilibrium. We present herein the study of an oligopeptide antibiotic distamycin, which binds to the minor groove of B-DNA. Chromatin mobility assays and circular dichroism spectroscopy have been employed to study the effect of distamycin on chromatosomes, isolated from the liver of Sprague-Dawley rats. Our results show that distamycin is capable of remodeling both chromatosomes and reconstituted nucleosomes, and the remodeling takes place in an ATP-independent manner. Binding of distamycin to the linker and nucleosomal DNA culminates in eviction of the linker histone and the formation of a population of off-centered nucleosomes. This hints at a possible corkscrew type motion of the DNA with respect to the histone octamer. Our results indicate that distamycin in spite of remodeling chromatin, inhibits transcription from both DNA and chromatin templates. Therefore, the DNA that is made accessible due to remodeling is either structurally incompetent for transcription, or bound distamycin poses a roadblock for the transcription machinery to advance.
Topics: Adenosine Triphosphate; Animals; Chromatin; Chromatin Assembly and Disassembly; Circular Dichroism; DNA; Distamycins; Histones; Male; Nucleic Acid Conformation; Protein Binding; Rats; Rats, Sprague-Dawley; Transcription, Genetic
PubMed: 23460895
DOI: 10.1371/journal.pone.0057693 -
Annals of Oncology : Official Journal... Dec 1994
Topics: Alkylation; Antineoplastic Agents; DNA, Neoplasm; Distamycins; Humans; Nitrogen Mustard Compounds
PubMed: 7696158
DOI: 10.1093/oxfordjournals.annonc.a058724