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Enterovirus 68 and Human Respiratory Infections
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
Janette C. Rahamat-Langendoen, Hubert G.M. Niesters
Protease inhibitors are another attractive target for antiviral therapy, because proteases are important in the viral replication cycle and because they have a unique and specific viral structure that is not present in host cell proteases.59,64 However, until now, only one drug (rupintrivir, Pfizer) has entered clinical trials (Figure 31.6). Rupintrivir showed strong in vitro antiviral capacity against a broad spectrum of rhinoviruses and enteroviruses.65 However, in phase II clinical trials, rupintrivir had only limited effect on virus reduction and disease severity in patients with experimental rhinovirus infection, thus halting further development for clinical use.62
Antimicrobial peptides and other peptide-like therapeutics as promising candidates to combat SARS-CoV-2
Published in Expert Review of Anti-infective Therapy, 2021
Masoumeh Sadat Mousavi Maleki, Mosayeb Rostamian, Hamid Madanchi
Peptidomimetics are more stable and more resistant to digestion than peptides. They also have more powerful drug-like properties, for example, they have higher bioavailability than natural peptides and their ability to cross the blood-brain barrier has been improved. They also show more flexibility for changes and modifications. Pharmacokinetics studies have shown that the clearance of peptidomimetics is lower than natural peptides, so they have a longer half-life in the body [135]. In this regard, due to the high similarity of human rhinoviruses 3C protease with coronaviruses 3CL protease, the question arises as to what is the inhibitory efficiency of rupintrivir, a HRV 3C protease inhibitor peptidomimetic, on SARS-CoV-2 protease? Vatansever et al. found that rupintrivir was able to inhibit SARS-CoV-2 virus 3CL protease with maximal inhibitory concentration (IC50) of approximately 67 μM. They also showed that the serum stability of rupintrivir was higher than other drugs studied [136]. We suggest that researchers pay more attention to AVPs and other peptide-like compounds, especially those discussed in this review article, for basic and clinical research in the field of COVID-19 control. Regarding the emergence need to combat COVID-19, we also recommend focusing on available FDA-approved peptide therapeutics which could be promising candidates for drug development studies and clinical trials for COVID-19.
Human rhinovirus infection and COPD: role in exacerbations and potential for therapeutic targets
Published in Expert Review of Respiratory Medicine, 2020
John Cafferkey, James Andrew Coultas, Patrick Mallia
Rupintrivir is a rhinovirus 3 C protease inhibitor and inactivation of 3 C leads to impaired HRV replication. Rupintrivir has demonstrated efficacy against multiple HRV serotypes including HRV-C in vitro [146,147], and in a phase II trial reduced symptom scores and viral titers in healthy volunteers undergoing experimental HRV infection with a good safety profile [148]. However since this clinical trial in 2003 no further clinical trials have been published.
Therapeutic targets for enterovirus infections
Published in Expert Opinion on Therapeutic Targets, 2020
Mira Laajala, Dhanik Reshamwala, Varpu Marjomäki
Since the viral proteins are translated as a single polyprotein, the next step in the viral life cycle is to process the polyprotein and release individual proteins, as well as some functional precursor proteins. Structural proteins VP0, VP3, and VP1 are needed for capsid assembly while non-structural proteins 2A, 2B, 2C, 3A, 3B, 3C, and 3D participate in other processes such as replication. The polyprotein processing is carried out by enterovirus encoded proteases 2A and 3C and a precursor protein 3CD. The primary cleavage between structural (P1) and non-structural (P2-P3) protein regions is carried out by 2A, while the 3C (or 3CD) protease carries out the other cleavages (reviewed in [46]). In addition to the polyprotein cleavage, the viral proteases have been shown to cleave different host cell factors in order to promote the infection (reviewed in [47]). Due to the important role of viral proteases in enterovirus pathogenicity, they have also been considered as potential antiviral targets, the focus being more in 3C protease. One of the most potential 3C protease inhibitors is a peptidomimetic irreversible 3C protease inhibitor called rupintrivir (AG7088), which was originally found to have antiviral activity against rhinoviruses [48]. However, later also other enteroviruses have been shown to be inhibited by rupintrivir and it has even entered phase II clinical trials [32,49,50]. Because of poor oral bioavailability of rupintrivir, also an orally bioavailable analogue, namely compound 1 (AG7404), was clinically tested [51,52]. However, the development of both protease inhibitors was eventually halted [52]. In addition to peptidomimetic inhibitors, also non-peptidomimetic inhibitors of EV-A71 3C protease, namely DC-07090 and quercetin, have been studied [53,54]. In yet another study, Wang et al. performed docking studies and in vitro protease inhibition experiments to understand the antiviral nature of 7-hydroxyflavone (HF) and its phosphate ester (FIP) against enterovirus 71, and found that the flavonoids derivatives target the 3C proteases of the virus [55]. In addition, although the development of antivirals against 2A viral protease has been rare, a recent study identified FDA-approved hepatitis C virus inhibitor, teleprevir, as a potential antiviral against the 2A protease of EV-D68 [56].