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      Investigational protease inhibitors as antiretroviral therapies

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      Expert Opinion on Investigational Drugs
      Informa UK Limited

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          Abstract

          <div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d10967381e158">Introduction</h5> <p id="P2">Highly Active Antiretroviral Therapy (HAART) has tremendously improved the life expectancy of the HIV-infected population over the past three decades. Protease inhibitors have been one of the major classes of drugs in HAART regimens that are effective in treating HIV. However, the emergence of resistance and cross-resistance against protease inhibitors encourages researchers to develop new PIs with broad-spectrum activity, as well as novel means of enhancing the efficacy of existing PIs. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d10967381e163">Areas covered</h5> <p id="P3">In this article we discuss recent advances in HIV protease inhibitor (PI) development, focusing on both investigational and experimental agents. We also include a section on pharmacokinetic booster drugs for improved bioavailability of protease inhibitors. Further, we discuss novel drug delivery systems using a variety of nanocarriers for the delivery of PIs across the blood-brain barrier to treat the HIV in the brain. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d10967381e168">Expert opinion</h5> <p id="P4">We discuss our opinion on the promises and challenges on the development of novel investigational and experimental PIs that are less toxic and more effective in combating drug-resistance. Further, we discuss the future of novel nanocarriers that have been developed to deliver PIs to the brain cells. Although these are promising findings, many challenges need to be overcome prior to making them a viable option. </p> </div>

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          Most cited references80

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          Drug resistance in brain diseases and the role of drug efflux transporters.

          Resistance to drug treatment is an important hurdle in the therapy of many brain disorders, including brain cancer, epilepsy, schizophrenia, depression and infection of the brain with HIV. Consequently, there is a pressing need to develop new and more effective treatment strategies. Mechanisms of resistance that operate in cancer and infectious diseases might also be relevant in drug-resistant brain disorders. In particular, drug efflux transporters that are expressed at the blood-brain barrier limit the ability of many drugs to access the brain. There is increasing evidence that drug efflux transporters have an important role in drug-resistant brain disorders, and this information should allow more efficacious treatment strategies to be developed.
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            Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS.

            HIV-1 protease inhibitors continue to play an important role in the treatment of HIV/AIDS, transforming this deadly ailment into a more manageable chronic infection. Over the years, intensive research has led to a variety of approved protease inhibitors for the treatment of HIV/AIDS. In this review, we outline current drug design and medicinal chemistry efforts toward the development of next-generation protease inhibitors beyond the currently approved drugs.
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              Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system

              HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % of HIV(+) patients despite the success of combination antiretroviral drug therapy (cART) in the periphery. Of note, potential toxicity of antiretroviral drugs in the central nervous system (CNS) remains remarkably underexplored and may contribute to the persistence of HAND in the cART era. Previous studies have shown antiretrovirals (ARVs) to be neurotoxic in the peripheral nervous system in vivo and in peripheral neurons in vitro. Alterations in lipid and protein metabolism, mitochondrial damage, and oxidative stress all play a role in peripheral ARV neurotoxicity. We hypothesized that ARVs also induce cellular stresses in the CNS, ultimately leading to neuronal damage and contributing to the changing clinical and pathological picture seen in HIV-positive patients in the cART era. In this report, we show that ARVs are neurotoxic in the CNS in both pigtail macaques and rats in vivo. Furthermore, in vitro, ARVs lead to accumulation of reactive oxygen species (ROS), and ultimately induction of neuronal damage and death. Whereas ARVs alone caused some activation of the endogenous antioxidant response in vitro, augmentation of this response by a fumaric acid ester, monomethyl fumarate (MMF), blocked ARV-induced ROS generation, and neuronal damage/death. These findings implicate oxidative stress as a contributor to the underlying mechanisms of ARV-induced neurotoxicity and will provide an access point for adjunctive therapies to complement ARV therapy and reduce neurotoxicity in this patient population.
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                Author and article information

                Journal
                Expert Opinion on Investigational Drugs
                Expert Opinion on Investigational Drugs
                Informa UK Limited
                1354-3784
                1744-7658
                September 02 2016
                October 02 2016
                August 02 2016
                October 02 2016
                : 25
                : 10
                : 1189-1200
                Article
                10.1080/13543784.2016.1212837
                5228633
                27415449
                b32e412e-1964-41be-a804-90f471de3b0f
                © 2016
                History

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