Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: July 2, 2019

Abstract Elimination of HIV-1 requires clearance and removal integrated proviral DNA from infected cells tissues. Here, sequential long-acting slow-effective release antiviral therapy (LASER ART) CRISPR-Cas9 demonstrate viral in latent infectious reservoirs humanized mice. subgenomic fragments, spanning the long terminal repeats Gag gene, are excised vivo, resulting elimination DNA; virus is not detected blood, lymphoid tissue, bone marrow brain by nested digital-droplet PCR as well RNAscope tests. No mediated off-target effects detected. Adoptive transfer human immunocytes dual treated, virus-free animals to uninfected mice fails produce progeny virus. In contrast, readily following sole LASER ART or treatment. These data provide proof-of-concept that permanent possible.

Language: Английский

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Fluorine-containing drugs approved by the FDA in 2021

Chinese Chemical Letters, Journal Year: 2022, Volume and Issue: 34(1), P. 107578 - 107578

Published: June 3, 2022

Language: Английский

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CRISPR editing of CCR5 and HIV-1 facilitates viral elimination in antiretroviral drug-suppressed virus-infected humanized mice

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(19)

Published: May 1, 2023

Treatment of HIV-1 ADA -infected CD34+ NSG-humanized mice with long-acting ester prodrugs cabotegravir, lamivudine, and abacavir in combination native rilpivirine was followed by dual CRISPR-Cas9 C-C chemokine receptor type five (CCR5) proviral DNA gene editing. This led to sequential viral suppression, restoration absolute human CD4 + T cell numbers, then elimination replication-competent virus 58% infected mice. Dual CRISPR therapies enabled the excision integrated cells contained within live animals. Highly sensitive nucleic acid nested droplet digital PCR, RNAscope, outgrowth assays affirmed elimination. not detected blood, spleen, lung, kidney, liver, gut, bone marrow, brain virus-free Progeny from adoptively transferred CRISPR-treated neither nor recovered. Residual fragments were easily seen untreated viral-rebounded No evidence off-target toxicities recorded any treated Importantly, therapy demonstrated statistically significant improvements cure percentages compared single treatments. Taken together, these observations underscore a pivotal role combinatorial editing achieving infection.

Language: Английский

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Long-acting parenteral drug delivery systems for the treatment of chronic diseases

Advanced Drug Delivery Reviews, Journal Year: 2023, Volume and Issue: 198, P. 114862 - 114862

Published: May 7, 2023

Language: Английский

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Creation of a long-acting nanoformulated dolutegravir

Nature Communications, Journal Year: 2018, Volume and Issue: 9(1)

Published: Jan. 24, 2018

Abstract Potent antiretroviral activities and a barrier to viral resistance characterize the human immunodeficiency virus type one (HIV-1) integrase strand transfer inhibitor dolutegravir (DTG). Herein, long-acting parenteral DTG was created through chemical modification improve treatment outcomes. A hydrophobic lipophilic modified prodrug is encapsulated into poloxamer nanoformulations (NMDTG) characterized by size, shape, polydispersity, stability. Retained intracytoplasmic NMDTG particles release drug from macrophages attenuate replication spread of CD4+ T cells. Pharmacokinetic tests in Balb/cJ mice show blood levels at, or above, its inhibitory concentration 90 64 ng/mL for 56 days, tissue 28 days. protects humanized challenge HIV-1 ADA strain two weeks. These results are first step towards producing use affecting apparent half-life, cell penetration, potency.

Language: Английский

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A year-long extended release nanoformulated cabotegravir prodrug

Nature Materials, Journal Year: 2020, Volume and Issue: 19(8), P. 910 - 920

Published: April 27, 2020

Language: Английский

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Long-acting antiretrovirals: a new era for the management and prevention of HIV infection

Journal of Antimicrobial Chemotherapy, Journal Year: 2021, Volume and Issue: 77(2), P. 290 - 302

Published: Aug. 17, 2021

The long-acting antiretroviral cabotegravir and rilpivirine combination has just received FDA, EMA Health Canada approval. This novel drug delivery approach is about to revolutionize the therapy of people living with HIV, decreasing 365 daily pill burden only six intramuscular injections per year. In addition, islatravir, a first-in-class nucleoside reverse transcriptase translocation inhibitor, intended be formulated as an implant dosing interval 1 year or more. At present, therapies (LA-ARTs) are given at fixed standard doses, irrespectively patient's weight BMI, without consideration for host genetic non-genetic factors likely influencing their systemic disposition. Despite few remaining challenges related administration (e.g. pain, dedicated medical procedure), development implementation LA-ARTs can overcome long-term adherence issues by improving patients' privacy reducing social stigma associated oral intake anti-HIV treatments. Yet, current 'one-size-fits-all' does not account recognized significant inter-individual variability in LA-ART pharmacokinetics. Therapeutic monitoring (TDM), important tool precision medicine, may provide physicians valuable information on actual exposure patients, contributing improve management real life. present review aims update state knowledge these promising discusses implications, particularly from clinical pharmacokinetics perspective, future prevention HIV infection, ongoing importance absence curative treatment effective vaccine.

Language: Английский

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Nanoparticulation of Prodrug into Medicines for Cancer Therapy

Advanced Science, Journal Year: 2021, Volume and Issue: 8(18)

Published: July 29, 2021

Abstract This article provides a broad spectrum about the nanoprodrug fabrication advances co‐driven by prodrug and nanotechnology development to potentiate cancer treatment. The inherits features of both concept nanomedicine know‐how, attempts solve underexploited challenge in treatment cooperatively. Prodrugs can release bioactive drugs on‐demand at specific sites reduce systemic toxicity, this is done using special properties tumor microenvironment, such as pH value, glutathione concentration, overexpressed enzymes; or exogenous stimulation, light, heat, ultrasound. nanotechnology, manipulating matter within nanoscale, has high relevance certain biological conditions, been widely utilized therapy. Together, marriage strategy which shield side effects parent drug with pinpoint delivery capability conceived highly camouflaged Trojan horse maneuver cancerous threats.

Language: Английский

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The Latest FDA-Approved Pharmaceuticals Containing Fragments of Tailor-Made Amino Acids and Fluorine

Pharmaceuticals, Journal Year: 2022, Volume and Issue: 15(8), P. 999 - 999

Published: Aug. 14, 2022

Nowadays, the selective introduction of fluorine into bioactive compounds is a mature strategy in design drugs allowing to increase efficiency, biological half-life and bio-absorption. On other hand, amino acids (AAs) represent one most ubiquitious classes naturally occurring organic compounds, which are found over 40% newly marked small-molecule pharmaceutical medical formulations. The primary goal this work underscore two major trends modern pharmaceuticals. first dealing with unique structural characteristics provided by structure featuring an abundance functionality presence stereogenic center, all bodes well for successful development targeted bioactivity. second related fine-tuning desired activity pharmacokinetics fluorine. Historically, both were developed separately as innovative prolific approaches drug design. However, recent decades, these clearly converging leading ever-increasing number approved pharmaceuticals containing features

Language: Английский

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Transformation of dolutegravir into an ultra-long-acting parenteral prodrug formulation

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: June 9, 2022

Abstract Ultra-long-acting integrase strand transfer inhibitors were created by screening a library of monomeric and dimeric dolutegravir (DTG) prodrug nanoformulations. This led to an 18-carbon chain modified ester nanocrystal (coined NM2DTG) with the potential sustain yearly dosing. Here, we show that physiochemical pharmacokinetic (PK) formulation properties facilitate slow drug release from tissue macrophage depot stores at muscle injection site adjacent lymphoid tissues following single parenteral injection. Significant plasma levels are recorded up year Tissue sites for hydrolysis dependent on dissolution release, drug-depot volume, perfusion, cell-tissue pH. Each affect extended NM2DTG apparent half-life PK parameters. The product can impact therapeutic adherence, tolerability, access widely used inhibitor in both resource limited rich settings reduce HIV-1 transmission achieve optimal treatment outcomes.

Language: Английский

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