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Nonclinical and clinical characterization of the absorption, metabolism, and excretion of islatravir.
Antimicrob Agents Chemother
January 2025
Merck & Co., Inc, Rahway, New Jersey, USA.
The development of new and improved antiretroviral therapies that allow for alternative dosing schedules is needed for people living with HIV-1. Islatravir is a deoxyadenosine analog in development for the treatment of HIV-1 that suppresses HIV-1 replication via multiple mechanisms of action, including reverse transcriptase translocation inhibition and delayed chain termination. Islatravir is differentiated from other HIV-1 antiretrovirals by its high potency, long , broad tissue distribution, and favorable drug resistance profile.
View Article and Find Full Text PDFThe activation cascade of the broad-spectrum antiviral bemnifosbuvir characterized at atomic resolution.
PLoS Biol
August 2024
Aix Marseille Université, CNRS, AFMB, UMR 7257, Marseille, France.
Bemnifosbuvir (AT-527) and AT-752 are guanosine analogues currently in clinical trials against several RNA viruses. Here, we show that these drugs require a minimal set of 5 cellular enzymes for activation to their common 5'-triphosphate AT-9010, with an obligate order of reactions. AT-9010 selectively inhibits essential viral enzymes, accounting for antiviral potency.
View Article and Find Full Text PDF4'-Ethynyl-2'-Deoxycytidine (EdC) Preferentially Targets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress.
Mol Cancer Ther
May 2024
Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Anticancer nucleosides are effective against solid tumors and hematologic malignancies, but typically are prone to nucleoside metabolism resistance mechanisms. Using a nucleoside-specific multiplexed high-throughput screening approach, we discovered 4'-ethynyl-2'-deoxycytidine (EdC) as a third-generation anticancer nucleoside prodrug with preferential activity against diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). EdC requires deoxycytidine kinase (DCK) phosphorylation for its activity and induces replication fork arrest and accumulation of cells in S-phase, indicating it acts as a chain terminator.
View Article and Find Full Text PDFMetabolism of third generation synthetic cannabinoids using zebrafish larvae.
Drug Test Anal
April 2022
Analytical Chemistry Department, Universitat de València, Burjassot, Spain.
Synthetic cannabinoids are the second largest group of new psychoactive substances reported by the United Nations Office on Drugs and Crime in the last decade and case reports bring attention to its high potency effects and its severe toxicity, including fatalities. Moreover, synthetic cannabinoids are usually entirely metabolized and metabolic pathways for many new generation synthetic cannabinoids are still unknown. In this study, the metabolism of five third generation synthetic cannabinoids was evaluated using zebrafish (Danio rerio) larvae as 24-h in vivo model studied within 5 days after fertilization.
View Article and Find Full Text PDFHighly-potent, synthetic APOBEC3s restrict HIV-1 through deamination-independent mechanisms.
PLoS Pathog
June 2021
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
The APOBEC3 (A3) genes encode cytidine deaminase proteins with potent antiviral and anti-retroelement activity. This locus is characterized by duplication, recombination, and deletion events that gave rise to the seven A3s found in primates. These include three single deaminase domain A3s (A3A, A3C, and A3H) and four double deaminase domain A3s (A3B, A3D, A3F, and A3G).
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