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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 -
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 -
Analytical Biochemistry Jan 2016Quantitative studies of the binding of various DNA-binding antibiotics with dsDNA are useful for drug design, not only for effective antibiotics, but also for antitumor...
Quantitative studies of the binding of various DNA-binding antibiotics with dsDNA are useful for drug design, not only for effective antibiotics, but also for antitumor drugs. We studied the binding kinetics, association and dissociation rate constants, and association constants (kon, koff, and Ka, respectively) of intercalators and groove binders, including various antibiotics, to double-stranded DNA (dA30·dT30 and dG30·dC30) immobilized on a highly sensitive 27 MHz quartz-crystal microbalance (QCM) in aqueous solution. Although a simple ethidium bromide intercalator bound to both dA30·dT30 and dG30·dC30, antibiotics that are side-binding intercalators, such as daunomycin, aclacinomycin A, and actinomycin D, with sugar or peptide moieties on the intercalator parts selectively bound to dG30·dC30 with high Ka and small koff values. Nogalamycin, a dumbbell-shaped penetrating intercalator, showed low kon and koff values owing to slow duplex unwinding during the penetration process. Groove binders (Hoechst 33258, distamycin A, and mithramycin) had high Ka values owing to the high kon values. Kinetic parameters depended largely on molecular shapes and DNA-binding molecule binding modes.
Topics: Anti-Bacterial Agents; DNA; Ethidium; Intercalating Agents; Kinetics; Quartz Crystal Microbalance Techniques
PubMed: 26408811
DOI: 10.1016/j.ab.2015.09.015 -
Acta Biochimica Et Biophysica Sinica Jan 2020Distamycin (DST) is a well-characterized DNA minor groove binder with antivirus activity and antitumor potency. Two separate gene clusters (a 28-kb cluster and a 7-kb...
Distamycin (DST) is a well-characterized DNA minor groove binder with antivirus activity and antitumor potency. Two separate gene clusters (a 28-kb cluster and a 7-kb cluster) have recently been identified to coordinately encode the biosynthetic machinery of DST in Streptomyces netropsis. Here we report a gene cassette, which is linked to the aforementioned smaller dst gene cluster and plays an important role in the self-resistance to DST in S. netropsis. This cassette consists of three uncharacterized genes that might be implicated in DNA replication/repair. Knockout of the cassette led to the decrease in the production of DST, while heterologous expression of part of the cassette in S. lividans made it become resistant to both DST and mitomycin C, another DNA-binding agent. More interestingly, homologs of these three genes were found in genomes of other actinomyces that produce DNA-binding antibiotics, suggesting that a novel common mechanism in addition to pumping may enable these strains to resist the cytotoxic metabolites they produced.
Topics: Anti-Bacterial Agents; Cells, Cultured; DNA Repair; DNA Replication; DNA-Binding Proteins; Distamycins; Drug Resistance, Bacterial; Escherichia coli; Gene Knockout Techniques; Genes, Bacterial; Mitomycin; Multigene Family; Streptomyces; Streptomyces lividans
PubMed: 31833535
DOI: 10.1093/abbs/gmz133 -
European Journal of Medicinal Chemistry Mar 2020Polyamides-based compounds related to the Streptomycetal distamycin and netropsin are potent cytostatic molecules that bind to AT-rich regions of the minor groove of the...
Polyamides-based compounds related to the Streptomycetal distamycin and netropsin are potent cytostatic molecules that bind to AT-rich regions of the minor groove of the DNA, hence interfering with DNA replication and transcription. Recently, derivatives belonging to this scaffold have been reported to halt the proliferation of deadly African trypanosomes by different and unrelated mechanisms. Here we describe the synthesis and preliminary characterization of the anti-trypanosomal mode of action of new potent and selective distamycin analogues. Two tri-heterocyclic derivatives containing a central N-methyl pyrrole ring (16 and 17) displayed high activity (EC < 20 nM) and selectivity (selectivity index >5000 with respect to mammalian macrophages) against the infective form of T. brucei. Both compounds caused cell cycle arrest by blocking the replication of the mitochondrial DNA but without affecting its integrity. This mode of action clearly differs from that reported for classical minor groove binder (MGB) drugs, which induce the degradation of the mitochondrial DNA. In line with this, in vitro assays suggest that 16 and 17 have a comparatively lower affinity for different template DNAs than the MGB drug diminazene. Therapeutic efficacy studies and stability assays suggest that the pharmacological properties of the hits should be optimized. The compounds can be rated as excellent scaffolds for the design of highly potent and selective anti-T. brucei agents.
Topics: Animals; Cell Cycle; Distamycins; Female; Macrophages; Mice; Mice, Inbred BALB C; Thiazoles; Trypanocidal Agents; Trypanosoma; Trypanosoma brucei brucei; Trypanosomiasis, African
PubMed: 31978782
DOI: 10.1016/j.ejmech.2020.112043 -
International Journal of Pharmaceutics Aug 2015Liposomes containing Distamycin A (DA) may be clinically useful in the treatment of ocular HSV infections, especially in acyclovir-resistant HSV keratitis. This study...
Liposomes containing Distamycin A (DA) may be clinically useful in the treatment of ocular HSV infections, especially in acyclovir-resistant HSV keratitis. This study evaluated the in vitro and in vivo performance of a topical controlled release liposomal formulation containing DA (DA-Lipo) aimed at reducing the toxicity of the encapsulated active agent and improving drug uptake by ocular tissues. The bioavailability of DA in the tear fluid and the DA uptake into the cornea were increased after instillation of DA-Lipo in rabbits, reaching the DA corneal concentration corresponding to IC50 values against HSV without any sign of transcorneal permeation of drug. DA-Lipo was definitely less cytotoxic then plain DA in rabbit corneal epithelial cells. These results provide new insights into the correlation between the in vitro data and the drug kinetics following ocular applications of liposomal vesicles.
Topics: Administration, Ophthalmic; Animals; Antiviral Agents; Aqueous Humor; Biological Availability; Cell Line; Cell Survival; Chlorocebus aethiops; Cornea; Distamycins; Herpesvirus 1, Human; Herpesvirus 2, Human; Liposomes; Male; Rabbits; Tears; Vero Cells
PubMed: 26183332
DOI: 10.1016/j.ijpharm.2015.05.055 -
Biochimie Feb 2019PA1 (dIm-PyPyβPyPyPy-γ-PyPyβPyPyPyPyβ-Ta) is a large (14-ring) hairpin polyamide that was designed to recognize the DNA sequence 5'-WGW-3', where W is either A or T....
PA1 (dIm-PyPyβPyPyPy-γ-PyPyβPyPyPyPyβ-Ta) is a large (14-ring) hairpin polyamide that was designed to recognize the DNA sequence 5'-WGW-3', where W is either A or T. As is common among the smaller 6-8-ring hairpin polyamides (PAs), it binds its target recognition sequence with low nM affinity. However, in addition to its large size, it is distinct from these more extensively characterized PAs in its high tolerance for mismatches and antiviral properties. In ongoing attempts to understand the basis for these distinctions, we conducted thermodynamics studies of PA1-DNA interactions. The temperature dependence of binding affinity was measured using TAMRA-labeled hairpin DNAs containing a single target sequence. PA1 binding to either an ATAT/TATA or an AAAA/TTTT pattern is consistently entropically driven. This is in contrast to the A/T pattern-dependent driving forces for DNA binding by netropsin, distamycin, and smaller hairpin polyamides. Analysis of the salt dependence of PA1-DNA binding reveals that within experimental error, there is no dependence on ionic strength, indicating that the polyelectrolyte effect does not contribute to PA1-DNA binding energetics. This is similar to that observed for smaller PAs. PA1-DNA recognition sequence binding stoichiometries were determined at both nM (fluorescence) and μM (circular dichroism) concentrations. With all sequences and under both conditions, multiple PA1 molecules bind the small DNA hairpin that contains only a single recognition sequence. Implications for these observations are discussed.
Topics: Antiviral Agents; DNA; Distamycins; Netropsin; Nylons; Thermodynamics
PubMed: 30481539
DOI: 10.1016/j.biochi.2018.11.013 -
Archives of Biochemistry and Biophysics Apr 2021Human telomerase that activates within cancer cells has a telomeric sequence at the 3' end. Each factor that stabilizes the G-quadruplex in guanine-rich telomeric...
Human telomerase that activates within cancer cells has a telomeric sequence at the 3' end. Each factor that stabilizes the G-quadruplex in guanine-rich telomeric sequences can inhibit the regular telomerase activity. Therefore, the telomeric G-quadruplex is known as a promising target in cancer treatment. In this work, we studied the binding of positively charged distamycin A and its uncharged derivative to the G-quadruplex in a solution environment by Molecular Dynamics (MD) simulation. The binding mechanism and subtle conformational changes were investigated as a result of the ligand attachment. Moreover, binding free energy and clustering analysis describe the stability and flexibility of G-quadruplexes upon ligand binding. Structural analyses displayed that the favorable binding of both ligands imposes significant stability and rigidity in G-quadruplex conformation compared to free G-quadruplex, especially charged distamycin. Hydration pattern and ion distribution were different for free G-quadruplex and both of the ligand complexes. Energy decomposition reveals the electrostatic effect on the stability of G-quadruplex. The radial distribution function displayed the solvent shell and ion moving away from the groove. The hydrogen bond played an essential role in the binding of both ligands, especially for the charged derivative. van der Waals interaction is the only factor that is more important in binding uncharged distamycin into G-quadruplex than the charged one. The calculated ΔG showed the stability of both ligands within grooves and good agreement with the experimental binding free energy data. Finally, the results suggest that ligand modification improves the binding mode toward stabilizing G-quadruplexes.
Topics: Antineoplastic Agents; Distamycins; G-Quadruplexes; Humans; Molecular Dynamics Simulation; Telomere
PubMed: 33607110
DOI: 10.1016/j.abb.2021.108797 -
Bioorganic & Medicinal Chemistry Letters Aug 2016A series of 47 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for anti-lung cancer activity by screening against the melanoma...
A series of 47 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for anti-lung cancer activity by screening against the melanoma cancer cell line B16-F10. Five compounds have been found to possess significant activity, more so than a standard therapy, Gemcitabine. Moreover, one compound has been found to have an activity around 70-fold that of Gemcitabine and has a favourable selectivity index of greater than 125. Furthermore, initial studies have revealed this compound to be metabolically stable and thus it represents a lead for further optimisation towards a novel treatment for lung cancer.
Topics: Antineoplastic Agents, Phytogenic; Biological Products; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Distamycins; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Molecular Structure; Structure-Activity Relationship; Gemcitabine
PubMed: 27349332
DOI: 10.1016/j.bmcl.2016.06.040