Dasatinib inhibits HIV-1 replication through the interference of SAMHD1 phosphorylation in CD4+ T cells

Bermejo, Mercedes; López-Huertas, María Rosa; García-Pérez, Javier; Climent, Núria; Descours, Benjamin; Ambrosioni, Juan; Mateos, Elena; Rodríguez-Mora, Sara; Rus-Bercial, Lucía; Benkirane, Monsef; Miró, José M.; Plana, Montserrat; Alcamı́, José; Coiras, Mayte

doi:10.1016/j.bcp.2016.02.002

Cited by 54 publications

(64 citation statements)

References 89 publications

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“…In addition to its role in regulating genome stability, SAMHD1 is best known for its ability to block infection of a broad range of retroviruses including human immunodeficiency virus type 1 (HIV-1). During viral infection, SAMHD1 depletes the cellular dNTPs needed for reverse transcription of the viral RNA genome (2)(3)(4)(5)(6)(7)(8). In the cell, SAMHD1 activity is modulated by allosteric activation and phosphorylation (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1

Knecht

Buzovetsky

Schneider³

et al. 2018

Preprint

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Abstract:SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that depletes cellular dNTPs in non-cycling cells to promote genome stability and to inhibit retroviral and herpes viral replication. In addition to being substrates, cellular nucleotides also allosterically regulate SAMHD1 activity. Recently, it was shown that high expression levels of SAMHD1 are also correlated with significantly worse patient responses to nucleotide analogue drugs important for treating a variety of cancers, including Acute Myeloid Leukemia (AML). In this study, we used biochemical, structural, and cellular methods to examine the interactions of various cancer drugs with SAMHD1. We found that both the catalytic and the allosteric sites of SAMHD1 are sensitive to sugar modifications of the nucleotide analogs, with the allosteric site being significantly more restrictive. We crystallized cladribine-TP, clofarabine-TP, fludarabine-TP, vidarabine-TP, cytarabine-TP, and gemcitabine-TP in the catalytic pocket of SAMHD1. We find that all of these drugs are substrates of SAMHD1 and that the efficacy of most of these drugs is affected by SAMHD1 activity. Of the nucleotide analogues tested, only cladribine-TP with a deoxyribose sugar efficiently induced the catalytically active SAMHD1 tetramer.Together, these results establish a detailed framework for understanding the substrate specificity and allosteric activation of SAMHD1 with regards to nucleotide analogues, which can be used to improve current cancer and antiviral therapies. SignificanceNucleoside analogue drugs are widely used to treat a variety of cancers and viral infections. With an essential role in regulating the nucleotide pool in the cell by degrading cellular nucleotides, SAMHD1 has the potential to decrease the cellular concentration of frequently prescribed nucleotide analogues and thereby decrease their clinical efficacy in cancer therapy. To improve future nucleotide analogue treatments, it is important to understand SAMHD1 interactions with these drugs. Our work thoroughly examines the extent to which nucleotide analogues interact with the catalytic and allosteric sites of SAMHD1. This work contributes to the assessment of SAMHD1 as a potential therapeutic target for cancer therapy and the future design of SAMHD1 modulators that might improve the efficacy of existing therapies.

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Section: Introductionmentioning

confidence: 99%

The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1

Knecht

Buzovetsky

Schneider³

et al. 2018

Preprint

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“…In 2014, Pogliaghi et al reported the reduction of HIV replication induced by dasatinib in vitro and suggested that this was mediated by the inhibition of activation and proliferation [13]. More recently, it has been shown that dasatinib is able to inhibit SAMHD1 phosphorylation in CD4 + T cells [14]. SAMHD1 is a cellular factor that acts as an innate antiviral restriction factor, and whose phosphorylation (that leads to inactivation) is induced by HIV.…”

Section: Tyrosine Kinase Inhibitors and Hiv-1mentioning

confidence: 99%

“…So far, in vitro and ex vivo results suggest that dasatinib is the most potent anti-HIV drug among the TKI family [14] in CD4T cells, without cell toxicity. Consequently, this drug should be chosen to be tested in pilot clinical trials.…”

Section: Tyrosine Kinase Inhibitors and Hiv-1mentioning

confidence: 99%

Potential role of tyrosine kinase inhibitors during primary HIV-1 infection

Ambrosioni

Coiras

Alcamı́

et al. 2017

Expert Review of Anti-infective Therapy

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“…Although mSAMHD1 and hSAMHD1 are highly similar in sequence and function, we found that mSAMHD1 possesses a more complex nucleotide-induced activation process, highlighting the regulatory role of the SAM domain. Our results provide new insights into the regulation of SAMHD1 activity, thereby will facilitate the improvement of HIV mouse models and the development of new therapies for certain cancers and autoimmune diseases.3The sterile alpha-motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is a dNTP phosphohydrolase that restricts viral replication by limiting the cellular dNTP pool [1][2][3][4][5][6][7] . Without an adequate supply of dNTPs, retroviruses like HIV-1 cannot complete reverse transcription.…”

mentioning

confidence: 99%

“…The sterile alpha-motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is a dNTP phosphohydrolase that restricts viral replication by limiting the cellular dNTP pool [1][2][3][4][5][6][7] . Without an adequate supply of dNTPs, retroviruses like HIV-1 cannot complete reverse transcription.…”

mentioning

confidence: 99%

The SAM domain of mouse SAMHD1 is critical for its activation and regulation

Buzovetsky

Tang

Knecht

et al. 2017

Preprint

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Human SAMHD1 (hSAMHD1) is a retroviral restriction factor that blocks HIV-1 infection by depleting the cellular nucleotides required for viral reverse transcription. SAMHD1 is allosterically activated by nucleotides that induce assembly of the active tetramer. Although the catalytic core of hSAMHD1 has been studied extensively, previous structures have not captured the regulatory SAM domain. In this study, we determined the first crystal structure of full-length SAMHD1 by capturing mouse SAMHD1 (mSAMHD1) structures in three different nucleotide bound states. Although mSAMHD1 and hSAMHD1 are highly similar in sequence and function, we found that mSAMHD1 possesses a more complex nucleotide-induced activation process, highlighting the regulatory role of the SAM domain. Our results provide new insights into the regulation of SAMHD1 activity, thereby will facilitate the improvement of HIV mouse models and the development of new therapies for certain cancers and autoimmune diseases.. CC-BY-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/208363 doi: bioRxiv preprint first posted online Oct. 24, 2017; 3 The sterile alpha-motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is a dNTP phosphohydrolase that restricts viral replication by limiting the cellular dNTP pool [1][2][3][4][5][6][7] . Without an adequate supply of dNTPs, retroviruses like HIV-1 cannot complete reverse transcription. In addition to its role in the antiviral response, SAMHD1 is also implicated in the autoimmune disease Aicardi-Goutieres syndrome (AGS). Homozygous mutations in the SAMHD1 gene lead to the accumulation of nucleotides in the cell and result in symptoms that mimic a congenital viral infection 8,9 . This highlights the importance of SAMHD1 activity in the human immune system and dNTP metabolism 6,10,11 .Like hSAMHD1, mSAMHD1 restricts HIV-1 through its dNTPase activity, and the activities of both enzymes are tightly regulated by an allosteric activation mechanism [12][13][14][15][16] . The active tetramer form of SAMHD1 is induced by cellular nucleotides, which bind two allosteric sites of each subunit. While allosteric site (Allo-site) 1 accommodates only GTP or dGTP, Allo-site 2 permits any dNTP 12,15,17 . The nucleotide-induced assembly of the SAMHD1 tetramer is necessary for its antiviral restriction activity [15][16][17] .Interestingly, the HD domain of hSAMHD1 was found to have higher enzymatic and antiviral activities than the full-length enzyme 15 , suggesting a potential regulatory role for the SAM domain. Without a structure of full-length SAMHD1, it has previously been difficult to determine the role of the SAM domain. In addition, despite past investigations on hSAMHD1, mechanisms for mSAMHD1 activation and viral restriction remain unclear.Two isoforms of mSAMHD1 resulting from alternative splicing share about 72-74% sequence identities with hSAMHD1 18 . These isofo...

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Dasatinib inhibits HIV-1 replication through the interference of SAMHD1 phosphorylation in CD4+ T cells

Cited by 54 publications

References 89 publications

The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1

The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1

Potential role of tyrosine kinase inhibitors during primary HIV-1 infection

The SAM domain of mouse SAMHD1 is critical for its activation and regulation

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