ABSTRACT
APE1 is a multifaceted protein that orchestrates multiple activities in the cell, one of which is the preservation of genomic integrity; a vital process that takes place in the context of the base excision repair (BER) pathway. Studies have implicated APE1 in rendering cancerous cells less vulnerable to the effects of DNA-damaging agents that are commonly used for the treatment of cancer. Furthermore, suppression of APE1 expression in cancer cell lines is accompanied by the potentiation of the activity of cytotoxic agents. As a result, major efforts have been directed towards the identification of small-molecule inhibitors of this DNA-repair enzyme. Herein, we review all patented small-molecule APE1 inhibitors reported prior to 2011. Unfortunately, the potency and selectivity of many of the reported inhibitors were not disclosed by the original authors, and at present it is unclear if APE1 is a bona fide target for many of the purported inhibitors. Moreover, cellular activity and toxicity of many inhibitors remain to be established. Since this is the first comprehensive review of small molecule APE1 inhibitors, we present all compounds reported to inhibit APE1 activity with an IC50 value ≤ 25 µM. Efforts towards a careful validation and optimization of these compounds are warranted. Furthermore, we explore potential allosteric drug-binding sites on the protein as an alternative approach for modulating the activity of this multifunctional protein. In addition, we give an overview of APE2, as well as other APE1 homologues in some disease-causing pathogens. Finally, given the universal importance of DNA repair, as well as the considerable conservation of repair proteins across all living organisms, we propose targeting the AP endonuclease activity of pathogens by the compounds discussed in this review, thereby expanding their therapeutic potential and application.
Subject(s)
DNA Repair/drug effects , DNA-(Apurinic or Apyrimidinic Site) Lyase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Small Molecule Libraries/chemistry , Catalytic Domain , DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism , Endonucleases , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Humans , Multifunctional Enzymes , Neoplasms/drug therapy , Neoplasms/enzymology , Small Molecule Libraries/therapeutic use , Structure-Activity RelationshipABSTRACT
We report here the discovery of a potent series of HIV-1 integrase (IN) inhibitors based on the ferrocenyl chalcone difluoridoborate structure. Ten new compounds have been synthesized and were generally found to have similar inhibitory activities against the IN 3' processing and strand transfer (ST) processes. IC(50) values were found to be in the low micromolar range, and significantly lower than those found for the non-coordinated ferrocenyl chalcones and other ferrocene molecules. The ferrocenyl chalcone difluoridoborates furthermore exhibited low cytotoxicity against cancer cells and low morphological activity against epithelial cells.
Subject(s)
Chalcones/chemistry , Chalcones/pharmacology , HIV Infections/drug therapy , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV Integrase/metabolism , HIV-1/drug effects , Borates/chemistry , Borates/pharmacology , Cell Line, Tumor , Chalcone , HIV-1/enzymology , HumansABSTRACT
HIV-1 integrase (IN) is a validated therapeutic target for antiviral drug design. However, the emergence of viral strains resistant to clinically studied IN inhibitors demands the discovery of novel inhibitors that are structurally as well mechanistically different. Herein, we describe the design and discovery of novel IN inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75, which is essential for the HIV-1 integration as an IN cofactor. By merging the pharmacophores of salicylate and catechol, the 2,3-dihydroxybenzamide (5a) was identified as a new scaffold to inhibit the strand transfer reaction efficiently. Further structural modifications on the 2,3-dihydroxybenzamide scaffold revealed that the heteroaromatic functionality attached on the carboxamide portion and the piperidin-1-ylsulfonyl substituted at the phenyl ring are beneficial for the activity, resulting in a low micromolar IN inhibitor (5p, IC(50)=5 µM) with more than 40-fold selectivity for the strand transfer over the 3'-processing reaction. More significantly, this active scaffold remarkably inhibited the interaction between IN and LEDGF/p75 cofactor. The prototype example, N-(cyclohexylmethyl)-2,3-dihydroxy-5-(piperidin-1-ylsulfonyl) benzamide (5u) inhibited the IN-LEDGF/p75 interaction with an IC(50) value of 8 µM. Using molecular modeling, the mechanism of action was hypothesized to involve the chelation of the divalent metal ions inside the IN active site. Furthermore, the inhibitor of IN-LEDGF/p75 interaction was properly bound to the LEDGF/p75 binding site on IN. This work provides a new and efficient approach to evolve novel HIV-1 IN inhibitors from rational integration and optimization of previously reported inhibitors.
Subject(s)
Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Catalytic Domain/drug effects , Catechols/chemical synthesis , HIV Integrase Inhibitors/chemical synthesis , HIV-1/drug effects , Receptor, Nerve Growth Factor/antagonists & inhibitors , Salicylates/chemical synthesis , Transcription Factors/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/analysis , Adaptor Proteins, Signal Transducing/drug effects , Adaptor Proteins, Signal Transducing/metabolism , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Catalytic Domain/genetics , Catechols/chemistry , Cell Line, Tumor , Drug Design , Drug Resistance, Multiple, Viral , Drug Screening Assays, Antitumor , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV-1/genetics , Humans , Metals/chemistry , Models, Molecular , Molecular Structure , Molecular Targeted Therapy , Receptor, Nerve Growth Factor/analysis , Receptor, Nerve Growth Factor/drug effects , Receptor, Nerve Growth Factor/metabolism , Salicylates/chemistry , Transcription Factors/analysis , Transcription Factors/drug effects , Transcription Factors/metabolismABSTRACT
The diketo acid (DKA) class of HIV-1 integrase (IN) inhibitors is thought to function by chelating divalent metal ions on the enzyme catalytic site. However, differences in mutations conferring resistance to various DKA inhibitors suggest that multiple binding orientations may exist. In order to facilitate identification of DKA binding sites, a series of photoactivable analogues of two potent DKAs was prepared as novel photoaffinity probes. In cross-linking assays designed to measure disruption of substrate DNA binding, the photoprobes behaved similarly to a reference DKA inhibitor. Molecular modeling studies suggest that such photoprobes interact within the IN active site in a manner similar to that of the parent DKAs. Analogues Ia-c are novel photoaffinity ligands useful in clarifying the HIV-1 binding interactions of DKA inhibitors.
Subject(s)
Cross-Linking Reagents/metabolism , HIV Integrase Inhibitors/metabolism , HIV Integrase/metabolism , Photosensitizing Agents/metabolism , Binding Sites , Cross-Linking Reagents/chemical synthesis , Cross-Linking Reagents/chemistry , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/chemistry , Molecular Structure , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Protein BindingABSTRACT
BACKGROUND: HIV-1 integrase (IN) represents a therapeutically advantageous viral target to treat HIV/AIDS in the clinic. Over a decade of progress in the field has resulted in IN inhibitor chemical classes that display specificity for strand transfer catalysis of the enzyme, thus blocking viral DNA integration into host cell nuclear DNA, an essential step for viral infectivity. OBJECTIVE: In this manuscript we provide an update on recent HIV-1 IN inhibitors that have been clinically evaluated, which include MK-0518, MK-2048, GS-9137, GS-9160, GS-9224, GSK-364735, and BMS-707035. The information presented here can aid in the IN drug developmental process. METHODS: We have limited the scope of this review to information available on the clinical evaluation of promising strand transfer-specific IN inhibitors and their potential drug-drug interaction profiles with other antiretroviral agents. RESULTS/CONCLUSION: The development of strand transfer-specific inhibitor classes is an important achievement for the IN drug design and development field. However, continued drug development is needed given that the ability of HIV to replicate under therapeutic pressure will undoubtedly lead to the emergence of IN drug-resistant viral strains.