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Molecular Aspects of Medicine Dec 2022Some medically important viruses-including retroviruses, flaviviruses, coronaviruses, and herpesviruses-code for a protease, which is indispensable for viral maturation... (Review)
Review
Some medically important viruses-including retroviruses, flaviviruses, coronaviruses, and herpesviruses-code for a protease, which is indispensable for viral maturation and pathogenesis. Viral protease inhibitors have become an important class of antiviral drugs. Development of the first-in-class viral protease inhibitor saquinavir, which targets HIV protease, started a new era in the treatment of chronic viral diseases. Combining several drugs that target different steps of the viral life cycle enables use of lower doses of individual drugs (and thereby reduction of potential side effects, which frequently occur during long term therapy) and reduces drug-resistance development. Currently, several HIV and HCV protease inhibitors are routinely used in clinical practice. In addition, a drug including an inhibitor of SARS-CoV-2 main protease, nirmatrelvir (co-administered with a pharmacokinetic booster ritonavir as Paxlovid®), was recently authorized for emergency use. This review summarizes the basic features of the proteases of human immunodeficiency virus (HIV), hepatitis C virus (HCV), and SARS-CoV-2 and discusses the properties of their inhibitors in clinical use, as well as development of compounds in the pipeline.
Topics: Humans; Viral Proteases; SARS-CoV-2; COVID-19; Antiviral Agents; HIV Infections
PubMed: 36459838
DOI: 10.1016/j.mam.2022.101159 -
Biomolecules Jul 2022Saquinavir was the first protease inhibitor developed for HIV therapy, and it changed the standard of treatment for this disease to a combination of drugs that... (Review)
Review
Saquinavir was the first protease inhibitor developed for HIV therapy, and it changed the standard of treatment for this disease to a combination of drugs that ultimately led to increased survival of this otherwise deadly condition. Inhibiting the HIV protease impedes the virus from maturing and replicating. With this in mind, since the start of the COVID-19 outbreak, the research for already approved drugs (mainly antivirals) to repurpose for treatment of this disease has increased. Among the drugs tested, saquinavir showed promise in silico and in vitro in the inhibition of the SARS-CoV-2 main protease (3CLpro). Another field for saquinavir repurposing has been in anticancer treatment, in which it has shown effects in vitro and in vivo in several types of cancer, from Kaposi carcinoma to neuroblastoma, demonstrating cytotoxicity, apoptosis, inhibition of cell invasion, and improvement of radiosensibility of cancer cells. Despite the lack of follow-up in clinical trials for cancer use, there has been a renewed interest in this drug recently due to COVID-19, which shows similar pharmacological pathways and has developed superior in silico models that can be translated to oncologic research. This could help further testing and future approval of saquinavir repurposing for cancer treatment.
Topics: HIV Infections; HIV Protease Inhibitors; Humans; Neoplasms; SARS-CoV-2; Saquinavir; COVID-19 Drug Treatment
PubMed: 35883499
DOI: 10.3390/biom12070944 -
Advanced Drug Delivery Reviews Aug 2016In spite of significant advances in antiretroviral (ARV) therapy, the elimination of human immunodeficiency virus (HIV) reservoirs from the periphery and the central... (Review)
Review
In spite of significant advances in antiretroviral (ARV) therapy, the elimination of human immunodeficiency virus (HIV) reservoirs from the periphery and the central nervous system (CNS) remains a formidable task. The incapability of ARV to go across the blood-brain barrier (BBB) after systemic administration makes the brain one of the dominant HIV reservoirs. Thus, screening, monitoring, and elimination of HIV reservoirs from the brain remain a clinically daunting and key task. The practice and investigation of nanomedicine possesses potentials for therapeutics against neuroAIDS. This review highlights the advancements in nanoscience and nanotechnology to design and develop specific size therapeutic cargo for efficient navigation across BBB so as to recognize and eradicate HIV brain reservoirs. Different navigation and drug release strategies, their biocompatibility and efficacy with related challenges and future prospects are also discussed. This review would be an excellent platform to understand nano-enable multidisciplinary research to formulate efficient nanomedicine for the management of neuroAIDS.
Topics: AIDS Dementia Complex; Anti-HIV Agents; Blood-Brain Barrier; Brain; HIV; Humans; Nanomedicine
PubMed: 26944096
DOI: 10.1016/j.addr.2016.02.008 -
The Canadian Journal of Infectious... 2022Since the beginning of the novel coronavirus (SARS-CoV-2) disease outbreak, there has been an increasing interest in discovering potential therapeutic agents for this... (Review)
Review
BACKGROUND
Since the beginning of the novel coronavirus (SARS-CoV-2) disease outbreak, there has been an increasing interest in discovering potential therapeutic agents for this disease. In this regard, we conducted a systematic review through an overview of drug development (in silico, in vitro, and in vivo) for treating COVID-19.
METHODS
A systematic search was carried out in major databases including PubMed, Web of Science, Scopus, EMBASE, and Google Scholar from December 2019 to March 2021. A combination of the following terms was used: coronavirus, COVID-19, SARS-CoV-2, drug design, drug development, In silico, In vitro, and In vivo. A narrative synthesis was performed as a qualitative method for the data synthesis of each outcome measure.
RESULTS
A total of 2168 articles were identified through searching databases. Finally, 315 studies (266 in silico, 34 in vitro, and 15 in vivo) were included. In studies with in silico approach, 98 article study repurposed drug and 91 studies evaluated herbal medicine on COVID-19. Among 260 drugs repurposed by the computational method, the best results were observed with saquinavir ( = 9), ritonavir ( = 8), and lopinavir ( = 6). Main protease ( = 154) following spike glycoprotein ( = 62) and other nonstructural protein of virus ( = 45) was among the most studied targets. Doxycycline, chlorpromazine, azithromycin, heparin, bepridil, and glycyrrhizic acid showed both in silico and in vitro inhibitory effects against SARS-CoV-2.
CONCLUSION
The preclinical studies of novel drug design for COVID-19 focused on main protease and spike glycoprotein as targets for antiviral development. From evaluated structures, saquinavir, ritonavir, eucalyptus, Tinospora cordifolia, aloe, green tea, curcumin, pyrazole, and triazole derivatives in in silico studies and doxycycline, chlorpromazine, and heparin from in vitro and human monoclonal antibodies from in vivo studies showed promised results regarding efficacy. It seems that due to the nature of COVID-19 disease, finding some drugs with multitarget antiviral actions and anti-inflammatory potential is valuable and some herbal medicines have this potential.
PubMed: 36199815
DOI: 10.1155/2022/2044282 -
Molecules (Basel, Switzerland) Sep 2023Natural compounds are rich in pharmacological properties that are a hot topic in pharmaceutical research. The quinoline ring plays important roles in many biological... (Review)
Review
Natural compounds are rich in pharmacological properties that are a hot topic in pharmaceutical research. The quinoline ring plays important roles in many biological processes in heterocycles. Many pharmacological compounds, including saquinavir and chloroquine, have been marketed as quinoline molecules with good anti-viral and anti-parasitic properties. Therefore, in this review, we summarize the medicinal chemistry of quinoline-modified natural product quinoline derivatives that were developed by several research teams in the past 10 years and find that these compounds have inhibitory effects on bacteria, viruses, parasites, inflammation, cancer, Alzheimer's disease, and others.
PubMed: 37764254
DOI: 10.3390/molecules28186478 -
Journal of Neuroimmune Pharmacology :... Mar 2021Despite the introduction of antiretroviral (ARV) therapy (ART), approximately 30-50% of people living with human immunodeficiency virus-1 (HIV-1) will develop a spectrum...
Despite the introduction of antiretroviral (ARV) therapy (ART), approximately 30-50% of people living with human immunodeficiency virus-1 (HIV-1) will develop a spectrum of measurable neurocognitive dysfunction, collectively called HIV-associated neurocognitive disorder (HAND). While the clinical manifestations of HAND have changed with the advent of ART, certain pathological features have endured, including white matter alterations and dysfunction. The persistence of white matter alterations in the post-ART era suggests that ARV drugs themselves may contribute to HAND pathology. Our group has previously demonstrated that two ARV compounds from the protease inhibitor (PI) class, ritonavir and lopinavir, inhibit oligodendrocyte maturation and myelin protein production. We hypothesized that other members of the PI class, saquinavir and darunavir, could also negatively impact oligodendrocyte differentiation. Here we demonstrate that treating primary rat oligodendrocyte precursor cells with therapeutically relevant concentrations of either ARV drug results in a concentration-dependent inhibition of oligodendrocyte maturation in vitro. Furthermore, we show that acidifying endolysosomal pH via a mucolipin transient receptor potential channel 1 (TRPML1) agonist provides protection against saquinavir- and darunavir-induced inhibition of oligodendrocyte maturation. Moreover, our findings suggest, for the first time, an imperative role of proper endolysosomal pH in regulating OL differentation, and that therapeutic targeting of endolysosomes may provide protection against ARV-induced oligodendrocyte dysregulation. Graphical Abstract Treatment of primary rat oligodendrocyte precursor cells with therapeutically relevant concentrations of either antiretroviral compound of the protease inhibitor class, darunavir or saquinavir, results in a concentration-dependent inhibition of oligodendrocyte maturation in vitro. Additionally, in darunavir or saquinavir-treated cultures we observed a concentration-dependent decrease in the number of acidic lysosomes, via immunostaining with LysoTracker Red, compared with vehicle-treated cultures. Finally, we showed that acidifying endolysosomal pH via a mucolipin transient receptor potential channel 1 (TRPML1) agonist provides protection against saquinavir- or darunavir-induced inhibition of oligodendrocyte maturation. Our findings suggest, for the first time, a critical role of proper endolysosomal pH in regulating OL differentation, and that therapeutic targeting of endolysosomes may provide protection against antiretroviral-induced oligodendrocyte dysregulation.
Topics: Animals; Apoptosis; Cell Differentiation; Cells, Cultured; Darunavir; Depression, Chemical; Dose-Response Relationship, Drug; Endosomes; HIV Protease Inhibitors; Hydrogen-Ion Concentration; Lysosomes; Myelin Proteins; Oligodendroglia; Oxidative Stress; Phthalimides; Quinolines; Rats; Rats, Sprague-Dawley; Saquinavir; Transient Receptor Potential Channels
PubMed: 31776836
DOI: 10.1007/s11481-019-09893-8 -
Clinical and Translational Science Jul 2022Although rifampin drug-drug interaction (DDI) studies are routinely conducted, there have been instances of liver function test (LFT) elevations, warranting further... (Review)
Review
Although rifampin drug-drug interaction (DDI) studies are routinely conducted, there have been instances of liver function test (LFT) elevations, warranting further evaluation. A literature review was conducted to identify studies in which combination with rifampin resulted in hepatic events and evaluate any similarities. Over 600 abstracts and manuscripts describing rifampin DDI studies were first evaluated, of which 30 clinical studies reported LFT elevations. Out of these, 11 studies included ritonavir in combination with other drug(s) in the rifampin DDI study. The number of subjects that were discontinued from treatment on these studies ranged from 0 to 71 (0-100% of subjects in each study). The number of subjects hospitalized for adverse events in these studies ranged from 0 to 41 (0-83.67% of subjects in each study). LFT elevations in greater than 50% of subjects were noted during the concomitant administration of rifampin with ritonavir-boosted protease inhibitors and with lorlatinib; with labeled contraindication due to observed hepatotoxicity related safety findings only for saquinavir/ritonavir and lorlatinib. In the lorlatinib and ritonavir DDI studies, considerable LFT elevations were observed rapidly, typically within 24-72 h following co-administration. A possible sequence effect has been speculated, where rifampin induction prior to administration of the combination may be associated with increased severity of the LFT elevations. The potential role of rifampin in the metabolic activation of certain drugs into metabolites with hepatic effects needs to be taken into consideration when conducting rifampin DDI studies, particularly those for which the metabolic profiles are not fully elucidated.
Topics: Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Lactams, Macrocyclic; Liver Function Tests; Rifampin; Ritonavir
PubMed: 35470578
DOI: 10.1111/cts.13281