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Cureus Aug 2022Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging condition that involves genetic mutations, resulting in debilitating phenotypic features. The present... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging condition that involves genetic mutations, resulting in debilitating phenotypic features. The present state of knowledge on the molecular pathways that contribute to the pathophysiology of HGPS and the techniques being tested and to combat progerin toxicity have been discussed here. Nuclear morphological abnormalities, dysregulated gene expression, DNA repair deficiencies, telomere shortening, and genomic instability are all caused by progerin accumulation, all of which impair cellular proliferative capability. In addition, HGPS cells and preclinical animal models have revealed new information about the disease's molecular and cellular pathways and putative mechanisms involved in normal aging. This article has discussed the understanding of the molecular pathways by which progerin expression leads to HGPS and how the advanced therapy options for HGPS patients can help us understand and treat the condition.
PubMed: 36196312
DOI: 10.7759/cureus.28629 -
Gut Sep 2021Approximately 5% of individuals infected with hepatitis B virus (HBV) are coinfected with hepatitis D virus (HDV). Chronic HBV/HDV coinfection is associated with an... (Review)
Review
Approximately 5% of individuals infected with hepatitis B virus (HBV) are coinfected with hepatitis D virus (HDV). Chronic HBV/HDV coinfection is associated with an unfavourable outcome, with many patients developing liver cirrhosis, liver failure and eventually hepatocellular carcinoma within 5-10 years. The identification of the HBV/HDV receptor and the development of novel in vitro and animal infection models allowed a more detailed study of the HDV life cycle in recent years, facilitating the development of specific antiviral drugs. The characterisation of HDV-specific CD4+ and CD8+T cell epitopes in untreated and treated patients also permitted a more precise understanding of HDV immunobiology and possibly paves the way for immunotherapeutic strategies to support upcoming specific therapies targeting viral or host factors. Pegylated interferon-α has been used for treating HDV patients for the last 30 years with only limited sustained responses. Here we describe novel treatment options with regard to their mode of action and their clinical effectiveness. Of those, the entry-inhibitor bulevirtide (formerly known as myrcludex B) received conditional marketing authorisation in the European Union (EU) in 2020 (Hepcludex). One additional drug, the prenylation inhibitor lonafarnib, is currently under investigation in phase III clinical trials. Other treatment strategies aim at targeting hepatitis B surface antigen, including the nucleic acid polymer REP2139Ca. These recent advances in HDV virology, immunology and treatment are important steps to make HDV a less difficult-to-treat virus and will be discussed.
Topics: Adaptive Immunity; Animals; Hepatitis D; Hepatitis D, Chronic; Hepatitis Delta Virus; Humans; Immunity, Innate
PubMed: 34103404
DOI: 10.1136/gutjnl-2020-323888 -
Drugs Feb 2021Lonafarnib (Zokinvy™) is an orally active farnesyltransferase inhibitor developed by Eiger BioPharmaceuticals under license from Merck & Co. for the treatment of... (Review)
Review
Lonafarnib (Zokinvy™) is an orally active farnesyltransferase inhibitor developed by Eiger BioPharmaceuticals under license from Merck & Co. for the treatment of hepatitis D virus (HDV) infections, and progeria and progeroid laminopathies. The drug was originally discovered by Merck & Co as an investigational drug in oncology. In progeria, lonafarnib inhibits farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerin-like proteins in the nucleus and cellular cytoskeleton. In November 2020, lonafarnib received its first approval in the USA to reduce the risk of mortality in Hutchinson-Gilford Progeria Syndrome (HGPS) and for the treatment of processing-deficient progeroid laminopathies (with either heterozygous LMNA mutation with progerin-like protein accumulation, or homozygous or compound heterozygous ZMPSTE24 mutations) in patients ≥ 12 months of age with a body surface area (BSA) of ≥ 0.39 m. Lonafarnib is under regulatory review in the European Union. Clinical development for the treatment of HDV infections is underway in multiple countries. This article summarizes the milestones in the development of lonafarnib leading to this first approval.
Topics: Antiviral Agents; Enzyme Inhibitors; Farnesyltranstransferase; Hepatitis D; Humans; Piperidines; Progeria; Pyridines
PubMed: 33590450
DOI: 10.1007/s40265-020-01464-z -
JHEP Reports : Innovation in Hepatology Sep 2023Chronic infection with hepatitis delta virus (HDV) affects between 12-20 million people worldwide and represents the most severe form of viral hepatitis, leading to... (Review)
Review
Chronic infection with hepatitis delta virus (HDV) affects between 12-20 million people worldwide and represents the most severe form of viral hepatitis, leading to accelerated liver disease progression, cirrhosis and its complications, such as end-stage-liver disease and hepatocellular carcinoma. From the discovery of HDV in 1977 by Prof. Mario Rizzetto, knowledge on the HDV life cycle and mechanisms of viral spread has expanded. However, little is still known about the natural history of the disease, host-viral interactions, and the role of the immune system in HDV persistence. Diagnosis of HDV is still challenging due to a lack of standardised assays, while accurate viral load quantification is needed to assess response and endpoints of antiviral treatment. Until recently, interferon has represented the only treatment option in patients with chronic hepatitis delta; however, it is associated with low efficacy and a high burden of side effects. The discovery of the entry inhibitor bulevirtide has represented a breakthrough in HDV treatment, by demonstrating high rates of viral suppression in phase II and III trials, results which have been confirmed in real-world settings and in patients with compensated advanced liver disease. In the meantime, other compounds ( lonafarnib, new anti-hepatitis B virus drugs) are under development to provide alternative or combined strategies for HDV cure. The first international Delta Cure meeting was organised in Milan in October 2022 with the aim of sharing and disseminating the latest data; this review summarises key takeaway messages from state-of-the-art lectures and research data on HDV.
PubMed: 37593170
DOI: 10.1016/j.jhepr.2023.100818 -
Nature Communications Feb 2024Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly... (Review)
Review
Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC: 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor.
Topics: Animals; Female; Mice; Dibenzocycloheptenes; Drug Repositioning; Piperidines; Pyridines; Respiratory Syncytial Virus Infections; Viral Fusion Proteins
PubMed: 38332002
DOI: 10.1038/s41467-024-45241-y -
Biomedicine & Pharmacotherapy =... Aug 2023Prenyltransferases (PTases) are known to play a role in embryonic development, normal tissue homeostasis and cancer by posttranslationally modifying proteins involved in... (Review)
Review
Prenyltransferases (PTases) are known to play a role in embryonic development, normal tissue homeostasis and cancer by posttranslationally modifying proteins involved in these processes. They are being discussed as potential drug targets in an increasing number of diseases, ranging from Alzheimer's disease to malaria. Protein prenylation and the development of specific PTase inhibitors (PTIs) have been subject to intense research in recent decades. Recently, the FDA approved lonafarnib, a specific farnesyltransferase inhibitor that acts directly on protein prenylation; and bempedoic acid, an ATP citrate lyase inhibitor that might alter intracellular isoprenoid composition, the relative concentrations of which can exert a decisive influence on protein prenylation. Both drugs represent the first approved agent in their respective substance class. Furthermore, an overwhelming number of processes and proteins that regulate protein prenylation have been identified over the years, many of which have been proposed as molecular targets for pharmacotherapy in their own right. However, certain aspects of protein prenylation, such as the regulation of PTase gene expression or the modulation of PTase activity by phosphorylation, have attracted less attention, despite their reported influence on tumor cell proliferation. Here, we want to summarize the advances regarding our understanding of the regulation of protein prenylation and the potential implications for drug development. Additionally, we want to suggest new lines of investigation that encompass the search for regulatory elements for PTases, especially at the genetic and epigenetic levels.
Topics: Protein Prenylation; Proteins; Dimethylallyltranstransferase; Enzyme Inhibitors; Terpenes; Prenylation
PubMed: 37236024
DOI: 10.1016/j.biopha.2023.114915 -
ELife Mar 2023Clinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends the lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a...
Clinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends the lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a devastating condition that accelerates many characteristics of aging and results in premature death due to cardiovascular sequelae. The US Food and Drug Administration approved Zokinvy (lonafarnib) in November 2020 for treating these patients, yet a detailed examination of drug-associated effects on cardiovascular structure, properties, and function has remained wanting. In this paper, we report encouraging outcomes of daily post-weaning treatment with lonafarnib on the composition and biomechanical phenotype of elastic and muscular arteries as well as associated cardiac function in a well-accepted mouse model of progeria that exhibits severe perimorbid cardiovascular disease. Lonafarnib resulted in 100% survival of the treated progeria mice to the study end-point (time of 50% survival of untreated mice), with associated improvements in arterial structure and function working together to significantly reduce pulse wave velocity and improve left ventricular diastolic function. By contrast, neither treatment with the mTOR inhibitor rapamycin alone nor dual treatment with lonafarnib plus rapamycin improved outcomes over that achieved with lonafarnib monotherapy.
Topics: Mice; Animals; Progeria; Pulse Wave Analysis; Piperidines; Sirolimus; Lamin Type A
PubMed: 36930696
DOI: 10.7554/eLife.82728 -
The Journal of Neuroscience : the... Aug 2022Alzheimer's disease (AD) is characterized pathologically by the structural and functional impairments of synapses in the hippocampus, inducing the learning and memory...
Alzheimer's disease (AD) is characterized pathologically by the structural and functional impairments of synapses in the hippocampus, inducing the learning and memory deficiencies. Ras GTPase is closely related to the synaptic function and memory. This study was to investigate the effects of farnesyl transferase inhibitor lonafarnib on the synaptic structure and function in AD male mice and explore the potential mechanism. Our results showed 50 mg/kg lonafarnib (intraperitoneal) rescued the impaired spatial memory and improved the damaged synaptic transmission and plasticity of Aβ mice. In addition, lonafarnib ameliorated the morphology of synaptic dendrites and spines in Aβ mice. Furthermore, lonafarnib enhanced α7nAChR cell surface expression and phosphorylation of downstream Akt and CaMKII in Aβ mice, which were inhibited by α7nAChR antagonist methyl lycaconitine (MLA), and increased the phosphorylation of CREB in a CaMKII- but not ERK-dependent way. Lonafarnib enhanced hippocampal brain-derived neurotrophic factor (BDNF) concentration in Aβ mice, which was sensitive to MLA and KN93 (an inhibitor of CaMKII), but not related to ERK and Akt pathways. H-Ras, but not Rhes, was related to the lonafarnib induced improvement of α7nAChR cell surface expression and BDNF content. Interestingly, lonafarnib induced improvement of synaptic transmission, plasticity and spatial cognition in Aβ mice was abolished by BDNF deprivation with TrkB/Fc chimera protein. Our results indicate that lonafarnib can rescue the structural and functional impairments of synapses in the Aβ mice, which may be related to the improvement of BDNF content through the H-Ras-α7nAChR-dependent CaMKII-CREB pathway, leading to the improvement of spatial cognition. Alzheimer's disease (AD) is characterized pathologically by the structural and functional impairments of synapses in the hippocampus, inducing the learning and memory deficiencies. However, no effective drugs have not been developed for the treatment of AD synaptic. This study for the first time reported the beneficial effects of Ras inhibitor lonafarnib on the synaptic structure and function in AD mice, providing an alternative way for the treatment of "synaptic disease" in AD patients.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain-Derived Neurotrophic Factor; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Hippocampus; Male; Memory Disorders; Mice; Peptide Fragments; Piperidines; Proto-Oncogene Proteins c-akt; Pyridines; Spatial Memory; Synapses; Up-Regulation; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 35760529
DOI: 10.1523/JNEUROSCI.1989-21.2022