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Summary and Development of a New Approach to Senescence
Published in Nate F. Cardarelli, The Thymus in Health and Senescence, 2019
The error-catastrophe theory is based on the accumulation of encoding errors that affect the transcription and translation of critical enzymes, senescence thus being viewed as miscoding. Positive evidence is not only lacking, but also generally what is known tends to negate the theory. This concept likewise fails to explain the transformed cell. All of the “theories” at the most elementary level require a change in the genome. Gene “switches” that were in the “on” position must be shifted to the “off” position or perhaps vice versa.
Genomic Instability During Aging of Postmitotic Mammalian Cells
Published in Alvaro Macieira-Coelho, Molecular Basis of Aging, 2017
The error catastrophe theory22 is another variant of the somatic mutation theory of aging. Error theory considers the effects of mutations generating more mutations. For example, a random mutation in a DNA polymerase that increases copying mistakes will contribute to a higher mutation frequency. This type of feedback loop is predicted to give rise to an exponential type of increase in somatic mutations with age. Obviously, this theory is not easily tested in postmitotic mammalian cells in vivo. It would be difficult to determine if a few cells out of many are in some phase of a nonlinear increase of mutations, particularly if such cells were rather rapidly eliminated from the population by the accumulation of deleterious mutations.
Interferon Alpha
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Jason Grebely, Gregory Dore, William Sievert
Ribavirin almost certainly has multiple effects on HCV infection, but which of the many potential mechanisms are relevant is unclear. Ribavirin is a synthetic guanosine analog (see Chapter 259, Ribavirin) that is activated via intracellular phosphorylation to its active form, ribavirin triphosphate. However, it is interesting, ribavirin monotherapy has only a moderate and transient dose-dependent inhibitory effect on HCV replication in vivo (Pawlotsky et al., 2004). Clinically, ribavirin acts to decrease relapse in subjects responding to combination therapy with ribavirin and interferon alpha (Bronowicki et al., 2006), which may be associated with a shortened half-life of HCV-infected cells in the presence of interferon alpha. However, a number of other mechanisms of action for ribavirin have been proposed. In vitro data suggest that ribavirin has only a minimal direct impact on HCV replication, by weakly inhibiting the HCV RNA-dependent RNA polymerase (RdRp) which is required for the replication of HCV (Lau et al., 2002). Ribavirin also inhibits inosine monophosphate dehydrogenase (IMPDH), perhaps leading to the depletion of intracellular guanosine triphosphate (GTP), which is required for HCV viral RNA synthesis (Maag et al., 2001). Ribavirin may also have immunomodulatory effects, shifting the balance between T-helper types 1 and 2 responses toward a type 1 response (Hultgren et al., 1998), which is important in the eradication of HCV in both humans and chimpanzees (Neumann-Haefelin et al., 2005). Last, evidence from mathematical modeling of HCV viral kinetics during interferon alpha and ribavirin combination therapy suggests that ribavirin may render HCV virions less infectious (Dixit et al., 2004). Thus ribavirin may act to decrease the de novo susceptibility of uninfected hepato-cytes, while interferon alpha inhibits virus production. It is interesting that it has also been shown that ribavirin is an RNA mutagen and may increase the rate at which random nucleotide mutations are incorporated into the viral genome during HCV replication (Crotty et al., 2000). This may lead to a phenomenon called error catastrophe, in which there is a loss of viral fitness by the lethal accumulation of nucleotide mutations during HCV replication. However, no studies to date have demonstrated an increased mutagenesis of HCV during therapy with ribavirin (Chevaliez et al., 2005; Lutchman et al., 2004). Taken together, these data suggest ribavirin may act via a number of different mechanisms. Further research is required to fully understand the most important components attributable to the antiviral effect observed in the clinic.
Can proteomics-based approaches further help COVID-19 prevention and therapy?
Published in Expert Review of Proteomics, 2021
The pro-drug, EIDD-2801 (also called molnupiravir or MK-4482), derived from the ribonucleoside analog β-D-N4–hydroxycytidine, exerts antiviral effects by acting as a competitive alternate substrate for the viral RNA polymerase. This allows its incorporation into the viral RNA, thereby accumulating mutations in the viral RNA genome and inducing error catastrophe [24]. EIDD-2801 exerts both SARS-CoV-2 infection prophylaxis and treatment effects through the oral route of administration [25]. The drug is presently undergoing clinical trial phases 2 and 3. Additionally, multivalent nanobodies or variable domains of heavy-chain-only Abs have been designed by studying the detailed structures of their epitopes and binding modes to the S protein of SARS-CoV-2 as well as the mechanisms by which the virus fuses to the cell membrane through the S protein [26]. These multivalent nanobodies block SARS-CoV-2 infection and suppress their mutational escape by targeting two independent epitopes [26]. The deep learning approach to predict and design a multi-epitope vaccine (DeepVacPred) combines in silico immunoinformatics and deep neural network strategies. The DeepVacPred computational framework has predicted several potential vaccine subunits from the available SARS-CoV-2 spike protein sequence [27]. Moreover, in silico analysis of the immune system protein interactome associated with SARS-CoV-2 infection and severity has revealed several novel therapeutic targets for drug repurposing against COVID-19 [28]. Hence, proteomics combined with bioinformatics may serve as a novel tool for understanding COVID-19 pathogenesis and designing therapeutics and vaccines.
Therapeutic targets for enterovirus infections
Published in Expert Opinion on Therapeutic Targets, 2020
Mira Laajala, Dhanik Reshamwala, Varpu Marjomäki
Multiple inhibitors against 3Dpol have been studied, which can be categorized into two groups: nucleoside analogs and non-nucleoside inhibitors. One of the most known nucleoside analog is ribavirin, which has been approved by FDA as an antiviral drug to treat chronic hepatitis C virus infections [63,64]. The efficacy of ribavirin has also been shown with enteroviruses and being a nucleoside analog, ribavirin was suggested to have a mutagenic effect on virus replication [65]. This was later confirmed in a study where the effect of ribavirin was directly shown to cause error catastrophe and lethal mutagenesis [66]. However, other antiviral mechanisms have also been proposed for ribavirin. Studies with hepatitis C virus have suggested that the effect is through inhibition of a host cell enzyme, inosine monophosphate dehydrogenase, which participates in the synthesis of guanine nucleotides, and thus, ribavirin treatment results in the depletion of GTP pools [67,68]. Structurally similar to ribavirin is another nucleoside analog, namely favipiravir, which has been shown to inhibit the RNA polymerase of multiple RNA viruses, including enteroviruses (reviewed in [69]). Although structurally similar, the mechanism of action for ribavirin and favipiravir were shown to differ in a study with influenza virus [70]. In contrast to ribavirin, favipiravir showed stronger direct inhibition of the viral polymerase and no effect on the inosine monophosphate dehydrogenase, suggesting that favipiravir functions as an alternative substrate for the RNA polymerase, while ribavirin affects the nucleotide pools through the cellular enzyme [70]. According to De Clercq (2013), however, the different metabolic forms of favipiravir can have different targets. Host cell enzymes metabolize favipiravir into ribofuranosylmonophosphate form, whose minor target is the inosine monophosphate dehydrogenase, while the ribofuranosyltriphosphate form of favipiravir may compete with the NTPs during replication [71]. In addition, gemcitabine has been shown to prevent the infection of some enteroviruses [72]. For human rhinovirus, the efficacy was even shown in vivo and the antiviral activity of gemcitabine was suggested to be due to the limitation of the source of nucleotides during replication [73]. In addition, the infection of EV-A71 has been prevented using an adenosine analog NITD008 [74]. NITD008 also protected mice from severe EV-A71 infection and resistance assay showed mutations not only in 3Dpol but also in viral 3A protein in the presence of the compound [74].