Long‐acting and extended‐release implant and nanoformulations with a synergistic antiretroviral two‐drug combination controls <scp>HIV</scp>‐1 infection in a humanized mouse model

Beloor, Jagadish; Kudalkar, Shalley N.; Buzzelli, Gina; Yang, Fan; Mandl, Hanna K.; Rajashekar, Jyothi Krishnaswamy; Spasov, Krasimir A.; Jorgensen, William L.; Saltzman, W. Mark; Anderson, Karen S.; Kumar, Priti

doi:10.1002/btm2.10237

Cited by 6 publications

(2 citation statements)

References 32 publications

(85 reference statements)

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“…Both the Compound 55 formulations had the same clearance. The slower metabolism of Compound 55, as shown by the increased volume of distribution and low CL rate, enables sustained levels for viral control, as demonstrated in earlier research using free Compound 55 [151].…”

Section: Formulationmentioning

confidence: 88%

Strategies in the Design and Development of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Vanangamudi,

Palaniappan,

Kathiravan

et al. 2023

Viruses

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AIDS (acquired immunodeficiency syndrome) is a potentially life-threatening infectious disease caused by human immunodeficiency virus (HIV). To date, thousands of people have lost their lives annually due to HIV infection, and it continues to be a big public health issue globally. Since the discovery of the first drug, Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), to date, 30 drugs have been approved by the FDA, primarily targeting reverse transcriptase, integrase, and/or protease enzymes. The majority of these drugs target the catalytic and allosteric sites of the HIV enzyme reverse transcriptase. Compared to the NRTI family of drugs, the diverse chemical class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has special anti-HIV activity with high specificity and low toxicity. However, current clinical usage of NRTI and NNRTI drugs has limited therapeutic value due to their adverse drug reactions and the emergence of multidrug-resistant (MDR) strains. To overcome drug resistance and efficacy issues, combination therapy is widely prescribed for HIV patients. Combination antiretroviral therapy (cART) includes more than one antiretroviral agent targeting two or more enzymes in the life cycle of the virus. Medicinal chemistry researchers apply different optimization strategies including structure- and fragment-based drug design, prodrug approach, scaffold hopping, molecular/fragment hybridization, bioisosterism, high-throughput screening, covalent-binding, targeting highly hydrophobic channel, targeting dual site, and multi-target-directed ligand to identify and develop novel NNRTIs with high antiviral activity against wild-type (WT) and mutant strains. The formulation experts design various delivery systems with single or combination therapies and long-acting regimens of NNRTIs to improve pharmacokinetic profiles and provide sustained therapeutic effects.

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Section: Formulationmentioning

confidence: 88%

Strategies in the Design and Development of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Vanangamudi,

Palaniappan,

Kathiravan

et al. 2023

Viruses

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“…There is also renewed interest in hu-PBL mouse models for the exploration of new anti-HIV compounds [79,80]. However, as stated above, the original hu-PBL mouse model on the SCID background, based on the injection of PBLs, suffers from severe GvHD in cases of high chimerism [81], limiting the experimental time.…”

Section: Ad: Which Humanized Mouse Models Are Suitable For Testing No...mentioning

confidence: 99%

The Humanized Mouse Model: What Added Value Does It Offer for HIV Research?

et al. 2023

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In the early 2000s, novel humanized mouse models based on the transplantation of human hematopoietic stem and progenitor cells (HSPCs) into immunocompromised mice were introduced (hu mice). The human HSPCs gave rise to a lymphoid system of human origin. The HIV research community has greatly benefitted from these hu mice. Since human immunodeficiency virus (HIV) type 1 infection results in a high-titer disseminated HIV infection, hu mice have been of great value for all types of HIV research from pathogenesis to novel therapies. Since the first description of this new generation of hu mice, great efforts have been expended to improve humanization by creating other immunodeficient mouse models or supplementing mice with human transgenes to improve human engraftment. Many labs have their own customized hu mouse models, making comparisons quite difficult. Here, we discuss the different hu mouse models in the context of specific research questions in order to define which characteristics should be considered when determining which hu mouse model is appropriate for the question posed. We strongly believe that researchers must first define their research question and then determine whether a hu mouse model exists, allowing the research question to be studied.

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Injectable controlled‐release systems for the prevention and treatment of infectious diseases

Kunkel,

McHugh

2023

J Biomedical Materials Res

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Pharmaceutical drugs, including vaccines, pre‐ and post‐exposure prophylactics, and chronic drug therapies, are crucial tools in the prevention and treatment of infectious diseases. These drugs have the ability to increase survival and improve patient quality of life; however, infectious diseases still accounted for more than 10.2 million deaths in 2019 before the COVID‐19 pandemic. High mortality can be, in part, attributed to challenges in the availability of adequate drugs and vaccines, limited accessibility, poor drug bioavailability, the high cost of some treatments, and low patient adherence. A majority of these factors are logistical rather than technical challenges, providing an opportunity for existing drugs and vaccines to be improved through formulation. Injectable controlled‐release drug delivery systems are one class of formulations that have the potential to overcome many of these limitations by releasing their contents in a sustained manner to reduce the need for frequent re‐administration and improve clinical outcomes. This review provides an overview of injectable controlled drug delivery platforms, including microparticles, nanoparticles, and injectable gels, detailing recent developments using these systems for single‐injection vaccination, long‐acting prophylaxis, and sustained‐release treatments for infectious disease.

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Long‐acting and extended‐release implant and nanoformulations with a synergistic antiretroviral two‐drug combination controls HIV‐1 infection in a humanized mouse model

Abstract: This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as

Cited by 6 publications

References 32 publications

Strategies in the Design and Development of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Strategies in the Design and Development of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

The Humanized Mouse Model: What Added Value Does It Offer for HIV Research?

Injectable controlled‐release systems for the prevention and treatment of infectious diseases

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