Interfacial inhibitors

doi:10.1016/j.bmcl.2015.07.032

Bioorganic & Medicinal Chemistry Letters

Volume 25, Issue 18, 15 September 2015, Pages 3961-3965

https://doi.org/10.1016/j.bmcl.2015.07.032 Get rights and content

Abstract

Targeting macromolecular interface is a general mechanism by which natural products inactivate macromolecular complexes by stabilizing normally transient intermediates. Demonstrating interfacial inhibition mechanism ultimately relies on the resolution of drug-macromolecule structures. This review focuses on medicinal drugs that trap protein–DNA complexes by binding at protein–DNA interfaces. It provides proof-of-concept and detailed structural and mechanistic examples for topoisomerase inhibitors and HIV integrase inhibitors. Additional examples of recent interfacial inhibitors for protein–DNA interfaces are provided, as well as prospects for targeting previously ‘undruggable’ targets including transcription, replication and chromatin remodeling complexes. References and discussion are included for interfacial inhibitors of protein–protein interfaces.

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Acknowledgments

We acknowledge support from the Center for Cancer Research, the Intramural Program of the National Cancer Institute (Z01 BC 006161 and Z01 BC 007333) and the National Institute of General Medical Sciences Postdoctoral Research Associate (PRAT) Program, US National Institutes of Health.

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DNA topoisomerases are a group of enzymes omnipresent in all organisms. They maintain the DNA topology during replication, repair, recombination, and transcription. However, the structure of topoisomerase in protozoan parasites differs significantly from that of human topoisomerases; thus, this enzyme acts as a crucial target in drug development against parasitic diseases. Although the therapeutic potential of drugs targeting the parasitic topoisomerase is well known, to manage the shortcomings of currently available therapeutics and the emergence of drug resistance, the discovery of novel antiparasitic molecules is an urgent need. In this review, we describe various investigational and repurposed topoisomerase inhibitors developed against protozoan parasites over the past few years.
Functional mimicry revealed by the crystal structure of an eIF4A:RNA complex bound to the interfacial inhibitor, desmethyl pateamine A
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Interfacial inhibitors exert their biological effects through co-association with two macromolecules. The pateamine A (PatA) class of molecules function by stabilizing eukaryotic initiation factor (eIF) 4A RNA helicase onto RNA, resulting in translation initiation inhibition. Here, we present the crystal structure of an eIF4A1:RNA complex bound to an analog of the marine sponge-derived natural product PatA, C5-desmethyl PatA (DMPatA). One end of this small molecule wedges itself between two RNA bases while the other end is cradled by several protein residues. Strikingly, DMPatA interacts with the eIF4A1:RNA complex in an almost identical fashion as rocaglamide A (RocA), despite being completely unrelated from a structural standpoint. The structural data rationalize the ability of PatA analogs to target a wider range of RNA substrates compared to RocA. We define the molecular basis of how DMPatA is able to clamp eIF4A1 onto RNA, imparting potent inhibitory properties to this molecule.
Lipid-derived electrophiles mediate the effects of chemotherapeutic topoisomerase I poisons
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Topoisomerase 1 (Top1) reversibly nicks chromosomal DNA to relax strain accumulated during transcription, replication, chromatin assembly, and chromosome condensation. The Top1 poison camptothecin targets cancer cells by trapping the enzyme in the covalent complex Top1_cc, tethered to cleaved DNA by a tyrosine-3′-phosphate bond. In vitro mechanistic studies point to interfacial inhibition, where camptothecin binding to the Top1-DNA interface stabilizes Top1_cc. Here we present a complementary covalent mechanism that is critical in vivo. We observed that camptothecins induce oxidative stress, leading to lipid peroxidation, lipid-derived electrophile accumulation, and Top1 poisoning via covalent modification. The electrophile 4-hydroxy-2-nonenal can induce Top1_cc on its own and forms a Michael adduct to a cysteine thiol in the Top1 active site, potentially blocking tyrosine dephosphorylation and 3′ DNA phosphate release. Thereby, camptothecins may leverage a physiological cysteine-based redox switch in Top1 to mediate their selective toxicity to rapidly proliferating cancer cells.
Topoisomerase IB poisons induce histone H2A phosphorylation as a response to DNA damage in Leishmania infantum
2019, International Journal for Parasitology: Drugs and Drug Resistance
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.
The Translation Inhibitor Rocaglamide Targets a Bimolecular Cavity between eIF4A and Polypurine RNA
2019, Molecular Cell
A class of translation inhibitors, exemplified by the natural product rocaglamide A (RocA), isolated from Aglaia genus plants, exhibits antitumor activity by clamping eukaryotic translation initiation factor 4A (eIF4A) onto polypurine sequences in mRNAs. This unusual inhibitory mechanism raises the question of how the drug imposes sequence selectivity onto a general translation factor. Here, we determined the crystal structure of the human eIF4A1⋅ATP analog⋅RocA⋅polypurine RNA complex. RocA targets the “bi-molecular cavity” formed characteristically by eIF4A1 and a sharply bent pair of consecutive purines in the RNA. Natural amino acid substitutions found in Aglaia eIF4As changed the cavity shape, leading to RocA resistance. This study provides an example of an RNA-sequence-selective interfacial inhibitor fitting into the space shaped cooperatively by protein and RNA with specific sequences.
Substituted 1,5-naphthyridine derivatives as novel antileishmanial agents. Synthesis and biological evaluation
2018, European Journal of Medicinal Chemistry
Citation Excerpt :
The reaction without catalyst did not work and the starting products were recovered. However, the use of trifluorboroetherate as Lewis acid catalyst gave us good results: the optimal ones were when 2 equivalents of Lewis acid were used and only 2,4-disubstituted 1,5-naphthyridines 17–31 were regioselectively obtained (Chart 2) when terminal alkynes were used (R2 = H, Chart 1), while the formation of the other regioisomers, namely 2,3-disubstituted 1,5-naphthyridines was not observed [27]. It is noteworthy that not only terminal alkynes 10–14 (Chart 1) can be used for the synthesis of 1,5-naphthyridines 17–31 but also internal alkyne 15 is appropriate for the formation of corresponding heterocyclic compounds, such as naphthyridine 32 (Chart 2).
Visceral leishmaniasis is a parasitic disease that affects, among other areas, both sides of the Mediterranean Basin. The drugs classically used in clinical practice are pentavalent antimonials (Sb^V) and amphotericin B, which are nephrotoxic, require parenteral administration, and increasing drug resistance in visceral leishmaniasis has been observed. These circumstances justify the search of new families of compounds to find effective drugs against the disease. Eukaryotic type I DNA topoisomerase (TopIB) has been found essential for the viability of the parasites, and therefore represents a promising target in the development of an antileishmanial therapy. In this search, heterocyclic compounds, such as 1,5-naphthyridines, have been prepared by cycloaddition reaction between N-(3-pyridyl)aldimines and acetylenes and their antileishmanial activity on promastigotes and amastigote-infected splenocytes of Leishmania infantum has been evaluated.
In addition, the cytotoxic effects of newly synthesized compounds were assessed on host murine splenocytes in order to calculate the corresponding selective indexes (SI). Excellent antileishmanial activity of 1,5-naphthyridine 19, 21, 22, 24 and 27 has been observed with similar activity than the standard drug amphotericin B and higher selective index (SI > 100) towards L. infantum amastigotes than amphotericin B (SI > 62.5). Special interest shows the 1,5-naphthyridine 22 with an IC₅₀ value (0.58 ± 0.03 μM) similar to the standard drug amphotericin B (0.32 ± 0.05 μM) and with the highest selective index (SI = 271.5). In addition, this compound shows remarkable inhibition on leishmanial TopIB. However, despite these interesting results, further studies are needed to disclose other potential targets involved in the antileishmanial effect of these novel compounds.

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Published by Elsevier Ltd.

Interfacial inhibitors

Abstract

Graphical abstract

Section snippets

Acknowledgments

J. Biol. Chem.

Trends Pharmacol. Sci.

Trends Genetics: TIG

Chem. Biol.

Prog. Nucl. Acid Res. Mol. Biol.

J. Mol. Biol.

Adv. Pharmacol.

Cell

Bioorg. Med. Chem. Lett.

Cell

Mol. Cell.

Curr. Opin. Struct. Biol.

J. Mol. Biol.

Mol. Cell

Nucleic Acids Res.

Nucleic Acids Res.

Proc. Natl. Acad. Sci. U.S.A.

Science

Nature

Curr. Med. Chem. Anti-cancer Agents

Nat. Rev. Drug Disc.

EMBO Rep.

Nature

Nat. Rev. Mol. Cell Biol.

ACS Chem. Biol.