Bioengineering and semisynthesis of an optimized cyclophilin inhibitor for treatment of chronic viral infection.
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ABSTRACT:
SUBMITTER: Hansson MJ
PROVIDER: S-EPMC4336584 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cyclophilin (CyP) is a peptidyl prolyl cis/trans isomerase, catalyzing the cis-trans isomerization of proline residues in proteins. CyP plays key roles in several different aspects of cellular physiology including the immune response, transcription, mitochondrial function, cell death, and chemotaxis. In addition to these cellular events, a number of reports demonstrated that CyP plays a critical role in the life cycle of viruses, especially human immunodeficiency virus (HIV) and hepatitis C virus (HCV). These two viruses are significant causes of morbidity and mortality worldwide, but current therapies are often insufficient. CyP may provide a novel therapeutic target for the management and/or cure of these diseases, in particular HCV.
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Project description:BackgroundViral kinetic models have proven useful in characterizing treatment effectiveness during HCV therapy with interferon (IFN) as well as with direct-acting antivirals (DAAs).MethodsHere we use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with setrobuvir, a non-nucleosidic inhibitor of the HCV NS5B polymerase enzyme. Using PK data from three studies in healthy volunteers and PK and VK data from a Phase I study, where setrobuvir was administered for 3 days, we fitted a two-compartment PK model with first-order absorption and lag-time, an Emax pharmacodynamics model and a standard biphasic VK model.ResultsSetrobuvir's EC50 and Hill coefficient and the viral clearance rate were significantly different (P=0.014, P<0.001 and P=0.004, respectively) between patients infected with HCV subtypes 1b and 1a, leading to an increased viral load decline in patients infected with genotype 1b virus.ConclusionsUnderstanding the combined effects of PK/VK on the performance of a non-nucleoside polymerase inhibitor such as setrobuvir could provide valuable insights into their use in combination with other DAAs as well as to optimize future therapy. Further, our work suggests that patients infected with subtype 1a would need higher doses than those infected with subtype 1b to achieve the same effectiveness. Whether this is true for other non-nucleoside polymerase inhibitors needs to be examined.
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Project description:The control of retroviral infection by antiviral factors referred to as restriction factors has become an exciting area in infectious disease research. TRIM5alpha has emerged as an important restriction factor impacting on retroviral replication including HIV-1 replication in primates. TRIM5alpha has a tripartite motif comprising RING, B-Box and coiled coil domains. The antiviral alpha splice variant additionally encodes a B30.2 domain which is recruited to incoming viral cores and determines antiviral specificity. TRIM5 is ubiquitinylated and rapidly turned over by the proteasome in a RING dependent way. Protecting restricted virus from degradation, by inhibiting the proteasome, rescues DNA synthesis, but not infectivity, indicating that restriction of infectivity by TRIM5alpha does not depend on the proteasome but the early block to DNA synthesis is likely to be mediated by rapid degradation of the restricted cores. The peptidyl prolyl isomerase enzyme cyclophilin A isomerises a peptide bond on the surface of the HIV-1 capsid and impacts on sensitivity to restriction by TRIM5alpha from Old World monkeys. This suggests that TRIM5alpha from Old World monkeys might have a preference for a particular capsid isomer and suggests a role for cyclophilin A in innate immunity in general. Whether there are more human antiviral TRIMs remains uncertain although the evidence for TRIM19's (PML) antiviral properties continues to grow. A TRIM5-like molecule with broad antiviral activity in cattle suggests that TRIM mediated innate immunity might be common in mammals. Certainly the continued study of restriction of viral infectivity by antiviral host factors will remain of interest to a broad audience and impact on a variety of areas including development of animal models for infection, development of viral vectors for gene therapy and the search for novel antiviral drug targets.
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Project description:Nerve injuries remain clinically challenging, and allografts showed great promise. Decellularized nerve allografts possess excellent biocompatibility and biological activity. However, the vast majority of decellularization protocols were established for small-size rodent nerves and are not suitable for clinical application. We aimed at developing a new method of decellularizing large-diameter nerves suitable for human transplantation. Repeated rounds of optimization to remove immunogenic material and preserve the extracellular structure were applied to the porcine sciatic nerve. Following optimization, extensive in vitro analysis of the acellular grafts via immunocytochemistry, immunohistology, proteomics and cell transplantation studies were performed. Large segments (up to 8 cm) of the porcine sciatic nerve were efficiently decellularized and histology, microscopy and proteomics analysis showed sufficient preservation of the extracellular matrix, with simultaneous consistent removal of immunogenic material such as myelin, DNA and axons, and axonal growth inhibitory molecules. Cell studies also demonstrated the suitability of these acellular grafts for 3D cell culture studies and translation to future large animal studies and clinical trials. By using non-human donors for peripheral nerve transplantation, significant drawbacks associated with the gold standard can be eliminated while simultaneously preserving the beneficial features of the extracellular matrix.
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