The current toolbox for APOBEC drug discovery

Grillo, Michael J.; Jones, Katherine F.; Carpenter, Michael A.; Harris, Reuben S.; Harki, Daniel A.

doi:10.1016/j.tips.2022.02.007

Cited by 17 publications

(18 citation statements)

References 135 publications

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“…The cross-linked oligonucleotides (oligos) were then evaluated as A3 substrates and compared to a standard linear substrate by a nuclear magnetic resonance (NMR)-based assay. Real-time NMR assays are advantageous because they are direct, utilizing only A3 enzymes and oligos in a suitable buffer system, unlike many fluorescence-based assays where a secondary enzyme and a fluorescently modified oligo are used . The NMR-based assay yields directly the initial velocity of deamination of various ssDNA substrates, including the modified ones, in the presence of A3 enzymes.…”

Section: Methodsmentioning

confidence: 99%

“…Real-time NMR assays are advantageous because they are direct, utilizing only A3 enzymes and oligos in a suitable buffer system, unlike many fluorescence-based assays where a secondary enzyme and a fluorescently modified oligo are used. 33 The NMR-based assay yields directly the initial velocity of deamination of various ssDNA substrates, including the modified ones, in the presence of A3 enzymes. Consequently, the Michaelis–Menten kinetic model is used to characterize substrates and inhibitors of A3.…”

Section: Methodsmentioning

confidence: 99%

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Design, Synthesis, and Evaluation of a Cross-Linked Oligonucleotide as the First Nanomolar Inhibitor of APOBEC3A

et al. 2022

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Drug resistance is a major problem associated with anticancer chemo-and immunotherapies. Recent advances in the understanding of resistance mechanisms have revealed that enzymes of the APOBEC3 (A3) family contribute to the development of drug resistance in multiple cancers. A3 enzymes are polynucleotide cytidine deaminases that convert cytosine to uracil (C→U) in single-stranded DNA (ssDNA) and in this way protect humans against viruses and mobile retroelements. On the other hand, cancer cells use A3s, especially A3A and A3B, to mutate human DNA, and thus by increasing rates of evolution, cancer cells escape adaptive immune responses and resist drugs. However, as A3A and A3B are non-essential for primary metabolism, their inhibition opens up a strategy to augment existing anticancer therapies and suppress cancer evolution. To test our hypothesis that pre-shaped ssDNA mimicking the U-shape observed in ssDNA−A3 complexes can provide a better binder to A3 enzymes, a Cu(I)-catalyzed azide−alkyne cycloaddition was used to cross-link two distant modified nucleobases in ssDNA. The resultant cytosine-containing substrate, where the cytosine sits at the apex of the loop, was deaminated faster by the engineered C-terminal domain of A3B than a standard, linear substrate. The cross-linked ssDNA was converted into an A3 inhibitor by replacing the 2′-deoxycytidine in the preferred TCA substrate motif by 2′-deoxyzebularine, a known inhibitor of single nucleoside cytidine deaminases. This strategy yielded the first nanomolar inhibitor of engineered A3B CTD and wild-type A3A (K i = 690 ± 140 and 360 ± 120 nM, respectively), providing a platform for further development of powerful A3 inhibitors.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Evaluation of a Cross-Linked Oligonucleotide as the First Nanomolar Inhibitor of APOBEC3A

et al. 2022

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“…Different A3 proteins have diverse cellular localization patterns: A3A/C/H act both in the cytoplasm and in the nucleus; A3B only in the nucleus; A3D/F/G are active in the cytoplasm [94]. Given these critical functions, it is no surprise that the A3 family is being studied in the context of cancer, antiviral and immune-related drug discovery [95][96][97][98].…”

Section: Overview Of Apobec3 Functionsmentioning

confidence: 99%

The coevolution between APOBEC3 and retrotransposons in primates

2022

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Retrotransposons are genetic elements with the ability to replicate in the genome using reverse transcriptase: they have been associated with the development of different biological structures, such as the Central Nervous System (CNS), and their high mutagenic potential has been linked to various diseases, including cancer and neurological disorders. Throughout evolution and over time, Primates and Homo had to cope with infections from viruses and bacteria, and also with endogenous retroelements. Therefore, host genomes have evolved numerous methods to counteract the activity of endogenous and exogenous pathogens, and the APOBEC3 family of mutators is a prime example of a defensive mechanism in this context.In most Primates, there are seven members of the APOBEC3 family of deaminase proteins: among their functions, there is the ability to inhibit the mobilization of retrotransposons and the functionality of viruses. The evolution of the APOBEC3 proteins found in Primates is correlated with the expansion of two major families of retrotransposons, i.e. ERV and LINE-1.In this review, we will discuss how the rapid expansion of the APOBEC3 family is linked to the evolution of retrotransposons, highlighting the strong evolutionary arms race that characterized the history of APOBEC3s and endogenous retroelements in Primates. Moreover, the possible role of this relationship will be assessed in the context of embryonic development and brain-associated diseases.

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“…In the context of “controlling” the mutational events, the inhibition of specific APOBEC members that are overexpressed in many cancer types could be proposed [ 81 ]. However, it is important to point out that such a strategy would only prevent the acquisition of additional APOBEC-associated mutations, but it would not reverse those already acquired.…”

Section: Diagnostic and Therapeutic Considerationsmentioning

confidence: 99%

Unifying Different Cancer Theories in a Unique Tumour Model: Chronic Inflammation and Deaminases as Meeting Points

Hernández-Camarero

López-Ruiz

Marchal

et al. 2022

IJMS

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The increase in cancer incidences shows that there is a need to better understand tumour heterogeneity to achieve efficient treatments. Interestingly, there are several common features among almost all types of cancers, with chronic inflammation induction and deaminase dysfunctions singled out. Deaminases are a family of enzymes with nucleotide-editing capacity, which are classified into two main groups: DNA-based and RNA-based. Remarkably, a close relationship between inflammation and the dysregulation of these molecules has been widely documented, which may explain the characteristic intratumor heterogeneity, both at DNA and transcriptional levels. Indeed, heterogeneity in cancer makes it difficult to establish a unique tumour progression model. Currently, there are three main cancer models—stochastic, hierarchic, and dynamic—although there is no consensus on which one better resembles cancer biology because they are usually overly simplified. Here, to accurately explain tumour progression, we propose interactions among chronic inflammation, deaminases dysregulation, intratumor genetic heterogeneity, cancer phenotypic plasticity, and even the previously proposed appearance of cancer stem-like cell populations in the edges of advanced solid tumour masses (instead of being the cells of origin of primary malignancies). The new tumour development model proposed in this study does not contradict previously accepted models and it may open up a window to interesting therapeutic approaches.

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The current toolbox for APOBEC drug discovery

Cited by 17 publications

References 135 publications

Design, Synthesis, and Evaluation of a Cross-Linked Oligonucleotide as the First Nanomolar Inhibitor of APOBEC3A

Design, Synthesis, and Evaluation of a Cross-Linked Oligonucleotide as the First Nanomolar Inhibitor of APOBEC3A

The coevolution between APOBEC3 and retrotransposons in primates

Unifying Different Cancer Theories in a Unique Tumour Model: Chronic Inflammation and Deaminases as Meeting Points

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