| 1. |
- Abdelrazak Morsy, Mohammad Hamdy, et al.
(författare)
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SOX11 is a novel binding partner and endogenous inhibitor of SAMHD1 ara-CTPase activity in mantle cell lymphoma
- 2024
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 143:19, s. 1953-1964
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Tidskriftsartikel (refereegranskat)abstract
- Sterile alpha motif and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate triphosphohydrolase with ara-CTPase activity that confers cytarabine (ara -C) resistance in several hematological malignancies. Targeting SAMHD1's ara-CTPase activity has recently been demonstrated to enhance ara -C ef fi cacy in acute myeloid leukemia. Here, we identify the transcription factor SRY-related HMGbox containing protein 11 (SOX11) as a novel direct binding partner and fi rst known endogenous inhibitor of SAMHD1. SOX11 is aberrantly expressed not only in mantle cell lymphoma (MCL), but also in some Burkitt lymphomas. Coimmunoprecipitation of SOX11 followed by mass spectrometry in MCL cell lines identi fi ed SAMHD1 as the top SOX11 interaction partner, which was validated by proximity ligation assay. In vitro, SAMHD1 bound to the HMG box of SOX11 with low-micromolar af fi nity. In situ crosslinking studies further indicated that SOX11-SAMHD1 binding resulted in a reduced tetramerization of SAMHD1. Functionally, expression of SOX11 inhibited SAMHD1 ara-CTPase activity in a dose-dependent manner resulting in ara -C sensitization in cell lines and in a SOX11-inducible mouse model of MCL. In SOX11-negative MCL, SOX11-mediated ara-CTPase inhibition could be mimicked by adding the recently identi fi ed SAMHD1 inhibitor hydroxyurea. Taken together, our results identify SOX11 as a novel SAMHD1 interaction partner and its fi rst known endogenous inhibitor with potentially important implications for clinical therapy strati fi cation.
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| 2. |
- Lennerstrand, Johan, et al.
(författare)
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Biochemical studies on the mechanism of human immunodeficiency virus type 1 reverse transcriptase resistance to 1-(beta-D-dioxolane)thymine triphosphate
- 2007
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Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 51:6, s. 2078-2084
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Tidskriftsartikel (refereegranskat)abstract
- A large panel of drug-resistant mutants of human immunodeficiency virus type 1 reverse transcriptase (RT) was used to study the mechanisms of resistance to 1-(beta-d-dioxolane)thymine triphosphate (DOT-TP) and other nucleotide analogs. RT containing thymidine analog-associated mutations (TAM) or RT with a T69S-SG insertion in combination with TAM removed 3'-azido-3'-deoxythymidine-5'-monophosphate or tenofovir more efficiently than DOT-monophosphate from chain-terminated DNA primer/template through ATP-mediated pyrophosphorolysis. For non-ATP-dependent discrimination toward DOT-TP, high levels of resistance were found for RT bearing the Q151M mutation with family mutations, while RT bearing only the M184V or the Y115F mutation conferred no resistance to DOT-TP. A lower degree of resistance to DOT-TP than to tenofovir diphosphate or carbovir-TP was found for RT containing the K65R mutation. In the present studies, 1-(beta-d-dioxolane)guanine triphosphate, another nucleotide with a dioxolane sugar moiety, showed a resistance profile similar to that of DOT-TP. The results suggest that DOT, compared with other approved nucleoside analogs, is overall more resilient to mutations such as TAM, M184V, and K65R, which are commonly found in viruses derived from subjects failing multinucleoside therapy.
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| 3. |
- Schinazi, Raymond F., et al.
(författare)
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Approaches for the development of antiviral compounds : the case of hepatitis C virus
- 2009
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Ingår i: Antiviral Strategies. - Berlin, Heidelberg : Springer Berlin/Heidelberg. ; , s. 25-51
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Bokkapitel (refereegranskat)abstract
- Traditional methods for general drug discovery typically include evaluating random compound libraries for activity in relevant cell-free or cell-based assays. Success in antiviral development has emerged from the discovery of more focused libraries that provide clues about structure activity relationships. Combining these with more recent approaches including structural biology and computational modeling can work efficiently to hasten discovery of active molecules, but that is not enough. There are issues related to biology, toxicology, pharmacology, and metabolism that have to be addressed before a hit compound becomes nominated for clinical development. The objective of gaining early preclinical knowledge is to reduce the risk of failure in Phases 1, 2, and 3, leading to the goal of approved drugs that benefit the infected individual. This review uses hepatitis C virus (HCV), for which we still do not have an ideal therapeutic modality, as an example of the multidisciplinary efforts needed to discover new antiviral drugs for the benefit of humanity.
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| 4. |
- Schinazi, Raymond F., et al.
(författare)
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Selection and Characterization of HIV-1 with a Novel S68 Deletion in Reverse Transcriptase
- 2011
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Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 55:5, s. 2054-2060
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Tidskriftsartikel (refereegranskat)abstract
- Resistance to human immunodeficiency virus type 1 (HIV-1) represents a significant problem in the design of novel therapeutics and the management of treatment regimens in infected persons. Resistance profiles can be elucidated by defining modifications to the viral genome conferred upon exposure to novel nucleoside reverse transcriptase (RT) inhibitors (NRTI). In vitro testing of HIV-1(LAI)-infected primary human lymphocytes treated with beta-D-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine (DFC; Dexelvucitabine; Reverset) produced a novel deletion of AGT at codon 68 (S68 Delta) alone and in combination with K65R that differentially affects drug response. Dual-approach clone techniques utilizing TOPO cloning and pyrosequencing confirmed the novel S68 Delta in the HIV-1 genome. The S68 Delta HIV-1 RT was phenotyped against various antiviral agents in a heteropolymeric DNA polymerase assay and in human lymphocytes. Drug susceptibility results indicate that the S68 Delta displayed a 10- to 30-fold increase in resistance to DFC, lamivudine, emtricitabine, tenofovir, abacavir, and amdoxovir and modest resistance to stavudine, beta-D-2',3'-oxa-5-fluorocytidine, or 9-(beta-D-1,3-dioxolan-4-yl) guanine and remained susceptible to 3'-azido-3'-deoxythymidine, 2',3'-dideoxyinosine (ddI), 1-(beta-D-dioxolane) thymine (DOT) and lopinavir. Modeling revealed a central role for S68 in affecting conformation of the beta 3-beta 4 finger region and provides a rational for the selective resistance. These data indicate that the novel S68 Delta is a previously unrecognized deletion that may represent an important factor in NRTI multidrug resistance treatment strategies.
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