title: Toward the discovery of novel anti-HIV drugs. Second-generation inhibitors of the cellular ATPase DDX3 with improved anti-HIV activity: synthesis, structure-activity relationship analysis, cytotoxicity studies, and target validation.
abstract: A hit optimization protocol applied to the first nonnucleoside inhibitor of the ATPase activity of human DEAD-box RNA helicase DDX3 led to the design and synthesis of second-generation rhodanine derivatives with better inhibitory activity toward cellular DDX3 and HIV-1 replication. Additional DDX3 inhibitors were identified among triazine compounds. Biological data were rationalized in terms of structure-activity relationships and docking simulations. Antiviral activity and cytotoxicity of selected DDX3 inhibitors are reported and discussed. A thorough analysis confirmed human DDX3 as a valid anti-HIV target. The compounds described herein represent a significant advance in the pursuit of novel drugs that target HIV-1 host cofactors.
authors.affiliation: Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Federico
authors.initials: F
authors.lastname: Falchi
authors.forename: Marco
authors.initials: M
authors.lastname: Radi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Botta
authors.forename: Gianni
authors.initials: G
authors.lastname: Casaluce
authors.forename: Martina
authors.initials: M
authors.lastname: Bernardini
authors.forename: Hamid
authors.initials: H
authors.lastname: Irannejad
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Anna
authors.initials: A
authors.lastname: Garbelli
authors.forename: Alberta
authors.initials: A
authors.lastname: Samuele
authors.forename: Samantha
authors.initials: S
authors.lastname: Zanoli
authors.forename: José A
authors.initials: JA
authors.lastname: Esté
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Gonzalez
authors.forename: Elisa
authors.initials: E
authors.lastname: Zucca
authors.forename: Stefania
authors.initials: S
authors.lastname: Paolucci
authors.forename: Fausto
authors.initials: F
authors.lastname: Baldanti
authors.forename: Jan
authors.initials: J
authors.lastname: De Rijck
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D003198:Computer Simulation; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D055785:Gene Knockdown Techniques; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D012236:Rhodanine / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D035683:MicroRNAs; D014227:Triazines; D012236:Rhodanine; D053487:DEAD-box RNA Helicases