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1.
Int J Biol Macromol ; 256(Pt 1): 128401, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38007027

ABSTRACT

Leishmaniasis, caused by a protozoan parasite, is among humanity's costliest banes, owing to the high mortality and morbidity ratio in poverty-stricken areas. To date, no vaccine is available for the complete cure of the disease. Current chemotherapy is expensive, has undesirable side effects, and faces drug resistance limitations and toxicity concerns. The substantial differences in homology between leishmanial DNA topoisomerase IB compared with the human counterparts provided a new lead in the study of the structural determinants that can be targeted. Several research groups explored this molecular target, trying to fill the therapeutic gap, and came forward with various anti-leishmanial scaffolds. This article is a comprehensive review of knowledge about topoisomerases as an anti-leishmanial drug target and their inhibitors collected over the years. In addition to information on molecular targets and reported scaffolds, the review details the structure-activity relationship of described compounds with leishmanial Topoisomerase IB. Moreover, the work also includes information about the structure of the inhibitors, showing common interacting residues with leishmanial topoisomerases that drive their mode of action towards them. Finally, in search of topoisomerase inhibitors at the stage of clinical trials, we have listed all the drugs that have been in clinical trials against leishmaniasis.


Subject(s)
Leishmania , Leishmaniasis , Humans , DNA Topoisomerases/pharmacology , Leishmaniasis/drug therapy , DNA Topoisomerases, Type I/metabolism , Topoisomerase Inhibitors/pharmacology , Topoisomerase Inhibitors/therapeutic use
2.
IUBMB Life ; 75(1): 40-54, 2023 01.
Article in English | MEDLINE | ID: mdl-35499745

ABSTRACT

The hypoxic tumour microenvironment (hTME), arising from inadequate and chaotic vascularity, can present a major obstacle for the treatment of solid tumours. Hypoxic tumour cells compromise responses to treatment since they can generate resistance to radiotherapy, chemotherapy and immunotherapy. The hTME impairs the delivery of a range of anti-cancer drugs, creates routes for metastasis and exerts selection pressures for aggressive phenotypes; these changes potentially occur within an immunosuppressed environment. Therapeutic strategies aimed at the hTME include targeting the molecular changes associated with hypoxia. An alternative approach is to exploit the prevailing lack of oxygen as a principle for the selective activation of prodrugs to target cellular components within the hTME. This review focuses on the design concepts and rationale for the use of unidirectional Hypoxia-Activated Prodrugs (uHAPs) to target the hTME as exemplified by the uHAPs AQ4N and OCT1002. These agents undergo irreversible reduction in a hypoxic environment to active forms that target DNA topoisomerase IIα (TOP2A). This nuclear enzyme is essential for cell division and is a recognised chemotherapeutic target. An activated uHAP interacts with the enzyme-DNA complex to induce DNA damage, cell cycle arrest and tumour cell death. uHAPs are designed to overcome the shortcomings of conventional HAPs and offer unique pharmacodynamic properties for effective targeting of TOP2A in the hTME. uHAP therapy in combination with standard of care treatments has the potential to enhance outcomes by co-addressing the therapeutic challenge presented by the hTME.


Subject(s)
Neoplasms , Prodrugs , Humans , Prodrugs/pharmacology , Prodrugs/therapeutic use , Tumor Microenvironment , Cell Hypoxia , Neoplasms/drug therapy , Neoplasms/genetics , Hypoxia/drug therapy , DNA Topoisomerases/pharmacology
3.
Article in English | MEDLINE | ID: mdl-31563118

ABSTRACT

DNA topoisomerases are considered consolidated druggable targets against diseases produced by trypanosomatids. Several reports indicated that indenoisoquinolines, a family of non-camptothecinic based topoisomerase poisons, have a strong leishmanicidal effect both in vitro and in vivo in murine models of visceral leishmaniasis. The antileishmanial effect of the indenoisoquinolines implies several mechanisms that include the stabilization of the cleavage complex, histone H2A phosphorylation and DNA fragmentation. A series of 20 compounds with the indenoisoquinoline scaffold and several substituents at positions N6, C3, C8 and C9, were tested both in promastigotes and in intramacrophage splenic amastigotes obtained from an experimental murine infection. The antileishmanial effect of most of these compounds was within the micromolar or submicromolar range. In addition, the introduction of an N atom in the indenoisoquinoline ring (7-azaindenoisoquinolines) produced the highest selectivity index along with strong DNA topoisomerase IB inhibition, histone H2A phosphorylation and DNA-topoisomerase IB complex stabilization. This report shows for the first time the effect of a series of synthetic indenoisoquinolines on histone H2A phosphorylation, which represents a primary signal of double stranded DNA break in genus Leishmania.


Subject(s)
Cell Cycle Checkpoints/drug effects , DNA Damage , DNA Topoisomerases/pharmacology , Histones/metabolism , Isoquinolines/pharmacology , Leishmania infantum/drug effects , Animals , Blotting, Western , Cells, Cultured , DNA Damage/drug effects , Female , Histones/genetics , Isoquinolines/chemistry , Leishmania infantum/cytology , Leishmania infantum/genetics , Leishmania infantum/metabolism , Male , Mice , Mice, Inbred BALB C , Microscopy, Confocal , Phosphorylation/drug effects , Rabbits , S Phase/drug effects , Spleen/cytology
4.
Curr Protoc Pharmacol ; Chapter 3: Unit 3.3., 2012 Jun.
Article in English | MEDLINE | ID: mdl-22684721

ABSTRACT

Topoisomerases are nuclear enzymes that play essential roles in DNA replication, transcription, chromosome segregation, and recombination. All cells have two major forms of topoisomerases: type I enzymes, which make single-stranded cuts in DNA, and type II enzymes, which cut and pass double-stranded DNA. DNA topoisomerases are important targets of approved and experimental anti-cancer agents. The protocols described in this unit are for assays used to assess new chemical entities for their ability to inhibit both forms of DNA topoisomerase. Included are an in vitro assay for topoisomerase I activity based on relaxation of supercoiled DNA, and an assay for topoisomerase II based on the decatenation of double-stranded DNA. The preparation of mammalian cell extracts for assaying topoisomerase activity is described, along with a protocol for an ICE assay to examine topoisomerase covalent complexes in vivo, and an assay for measuring DNA cleavage in vitro.


Subject(s)
DNA Topoisomerases/metabolism , DNA, Catenated/drug effects , DNA, Superhelical/drug effects , Enzyme Assays/methods , Animals , Antigen-Antibody Complex/metabolism , Cell Extracts , Cell Membrane/immunology , Cells, Cultured , DNA Cleavage/drug effects , DNA Topoisomerases/pharmacology , DNA, Catenated/metabolism , DNA, Superhelical/metabolism , Electrophoresis, Polyacrylamide Gel/methods , Humans , Mice , Plasmids/pharmacology , Topoisomerase Inhibitors/pharmacology
5.
Enferm. infecc. microbiol. clín. (Ed. impr.) ; 25(supl.2): 38-47, oct. 2007. tab
Article in Spanish | IBECS | ID: ibc-177538

ABSTRACT

Las enterobacterias productoras de betalactamasas de espectro extendido (BLEE) no sólo son resistentes a los compuestos hidrolizados por estas enzimas, sino que con frecuencia presentan mecanismos adicionales que las hacen resistentes a cefamicinas, combinaciones de betalactámicos con inhibidores de betalactamasas e incluso carbapenemes. Las alteraciones de la permeabilidad y la producción de betalactamasas adicionales (incluidas las enzimas tipo AmpC y carbapenemasas) suelen ser las causas de esta resistencia incrementada a betalactámicos. La disminución de la permeabilidad como causa de resistencia se ha estudiado con mayor detalle en Klebsiella pneumoniae, organismo en el que la pérdida de las 2 porinas principales, OmpK35 y OmpK36, causa resistencia a cefoxitina e incremento en la resistencia a diversos betalactámicos y a otras familias de compuestos. Aunque no se conocen con detalle las causas de la pérdida de las porinas, se ha demostrado que para OmpK36 ello se relaciona con alteraciones estructurales del gen codificador, en especial su interrupción por una secuencia de inserción. Las tasas de resistencia a quinolonas, aminoglucósidos y cotrimoxazol también son mayores en las cepas que producen BLEE que en las que carecen de BLEE. La resistencia a quinolonas en cepas productoras de BLEE es multifactorial; intervienen en ella alteraciones en las topoisomerasas similares a las observadas en cepas sin BLEE, disminución de la permeabilidad, expresión de bombas de expulsión activa, y producción de proteínas mediadas por plásmidos de la familia Qnr (QnrA, QnrB, QnrS) o de la acetilasa AAC(6')-Ib-cr. La resistencia a aminoglucósidos suele estar relacionada con la producción de diferentes enzimas modificadoras de aminoglucósidos, codificadas por genes incluidos en integrones. También los integrones contienen genes causantes de resistencia a sulfamidas y a trimetoprim (implicados en la resistencia a cotrimoxazol) y en ocasiones a tetraciclinas


Extended-spectrum beta-lactamases (ESBL)-producing enterobacterias, in addition to being resistant to the compounds hydrolyzed by these enzymes, frequently present other mechanisms causing resistance to cephamycins, beta-lactam plus beta-lactamase inhibitor combinations and even carbapenems. The usual cause of this increased resistance to beta-lactams is altered permeability and production of additional beta-lactamases (including AmpC-type enzymes and carbapenemases). Decreased permeability as a cause of resistance has been studied in greatest detail in Klebsiella pneumoniae. In this species, simultaneous loss of the two major porins, namely OmpK35 and OmpK36, leads to cefoxitin resistance and increased resistance to several beta-lactams and other families of antimicrobial agents. Although the precise mechanisms involved in porin loss are poorly characterized, for OmpK36 this loss has been demonstrated to be related to structural alterations in the corresponding encoding gene, particularly interruption by insertion sequences. Resistance to quinolones, aminoglycosides and co-trimoxazole is also more common among ESBL-producing strains than in strains lacking these enzymes. Resistance to quinolones is multifactorial and is dependent on topoisomerase alterations similar to those found in organisms lacking ESBLs, decreased permeability, increased efflux, and production of plasmidmediated proteins of the Qnr family (QnrA, QnrB, QnrS), and AAC(6')-Ib-cr acetylase. Resistance to aminoglycosides is usually related to the production of distinct aminoglycoside-modifying enzymes encoded by integronborne genes. Integrons also contain genes coding for resistance to sulfamides and trimethoprim (involved in co-trimoxazole resistance) and sometimes tetracycline resistance genes


Subject(s)
beta-Lactam Resistance , beta-Lactamases/biosynthesis , Enterobacteriaceae Infections/drug therapy , Klebsiella pneumoniae/pathogenicity , Quinolones/pharmacology , DNA Topoisomerases/pharmacology , Cefoxitin/pharmacology
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