Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial

PLoS One

Fernando Tricta¹  John Connelly¹  Bernadette M. Cracchiolo¹  Michael B. Mathews²  Paul E. Palumbo³  Jonathan Karn³  Myung Hee Park³  Bart Holland⁴  Axel-Rainer Hanauske⁵  Hartmut M. Hanauske-Abel⁶  Deepti Saxena⁶  Michael Spino⁷  Darlene D’Alliessi Gandolfi⁸  Tsafi Pe’ery⁹ 

[1] ApoPharma Inc., Toronto, Ontario, Canada;Department of Chemistry, Manhattanville College, Purchase, New York, United States of America;Department of Medicine, New Jersey Medical School, Rutgers University, Newark, New Jersey, United States of America;Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America;Department of Obstetrics, Gynecology and Women’s Health, New Jersey Medical School, Rutgers University, Newark, New Jersey, United States of America;Department of Pediatrics, New Jersey Medical School, Rutgers University, Newark, New Jersey, United States of America;Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada;Oncology Center and Medical Clinic III, Asklepios Klinik St. Georg, Hamburg, Germany;Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institute of Health, Bethesda, Maryland, United States of America

关键词: HIV-1;    Apoptosis;    Antiretrovirals;    Viral load;    Drug therapy;    Primary cells;    Pharmacokinetics;    DNA fragmentation;   

DOI  :  10.1371/journal.pone.0154842

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Antiretrovirals suppress HIV-1 production yet spare the sites of HIV-1 production, the HIV-1 DNA-harboring cells that evade immune detection and enable viral resistance on-drug and viral rebound off-drug. Therapeutic ablation of pathogenic cells markedly improves the outcome of many diseases. We extend this strategy to HIV-1 infection. Using drug-based lead discovery, we report the concentration threshold-dependent antiretroviral action of the medicinal chelator deferiprone and validate preclinical findings by a proof-of-concept double-blind trial. In isolate-infected primary cultures, supra-threshold concentrations during deferiprone monotherapy caused decline of HIV-1 RNA and HIV-1 DNA; did not allow viral breakthrough for up to 35 days on-drug, indicating resiliency against viral resistance; and prevented, for at least 87 days off-drug, viral rebound. Displaying a steep dose-effect curve, deferiprone produced infection-independent deficiency of hydroxylated hypusyl-eIF5A. However, unhydroxylated deoxyhypusyl-eIF5A accumulated particularly in HIV-infected cells; they preferentially underwent apoptotic DNA fragmentation. Since the threshold, ascertained at about 150 μM, is achievable in deferiprone-treated patients, we proceeded from cell culture directly to an exploratory trial. HIV-1 RNA was measured after 7 days on-drug and after 28 and 56 days off-drug. Subjects who attained supra-threshold concentrations in serum and completed the protocol of 17 oral doses, experienced a zidovudine-like decline of HIV-1 RNA on-drug that was maintained off-drug without statistically significant rebound for 8 weeks, over 670 times the drug’s half-life and thus clearance from circulation. The uniform deferiprone threshold is in agreement with mapping of, and crystallographic 3D-data on, the active site of deoxyhypusyl hydroxylase (DOHH), the eIF5A-hydroxylating enzyme. We propose that deficiency of hypusine-containing eIF5A impedes the translation of mRNAs encoding proline cluster (‘polyproline’)-containing proteins, exemplified by Gag/p24, and facilitated by the excess of deoxyhypusine-containing eIF5A, releases the innate apoptotic defense of HIV-infected cells from viral blockade, thus depleting the cellular reservoir of HIV-1 DNA that drives breakthrough and rebound. Trial Registration: ClinicalTrial.gov NCT02191657.

【 授权许可】

CC BY