DPP4-directed therapeutic strategies for MERS-CoV

Reinhold, Dirk; Brocke, Stefan

doi:10.1016/s1473-3099(13)70696-0

Cited by 29 publications

(24 citation statements)

References 5 publications

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“…The S protein binds to the MERS-CoV receptor dipeptidyl peptidase 4 (DPP4, also called CD26) as a method for entry into the target cell (47). It encodes the determinants for both host range and cell tropism (46,47). Viral binding spares the hydrolase domain on DPP4, thus rendering drugs against this target ineffective for treatment.…”

Section: Discussionmentioning

confidence: 99%

A synthetic consensus anti–spike protein DNA vaccine induces protective immunity against Middle East respiratory syndrome coronavirus in nonhuman primates

et al. 2015

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First identified in 2012, Middle East respiratory syndrome (MERS) is caused by an emerging human coronavirus, which is distinct from the severe acute respiratory syndrome coronavirus (SARS-CoV), and represents a novel member of the lineage C betacoronoviruses. Since its identification, MERS coronavirus (MERS-CoV) has been linked to more than 1372 infections manifesting with severe morbidity and, often, mortality (about 495 deaths) in the Arabian Peninsula, Europe, and, most recently, the United States. Human-to-human transmission has been documented, with nosocomial transmission appearing to be an important route of infection. The recent increase in cases of MERS in the Middle East coupled with the lack of approved antiviral therapies or vaccines to treat or prevent this infection are causes for concern. We report on the development of a synthetic DNA vaccine against MERS-CoV. An optimized DNA vaccine encoding the MERS spike protein induced potent cellular immunity and antigen-specific neutralizing antibodies in mice, macaques, and camels. Vaccinated rhesus macaques seroconverted rapidly and exhibited high levels of virus-neutralizing activity. Upon MERS viral challenge, all of the monkeys in the control-vaccinated group developed characteristic disease, including pneumonia. Vaccinated macaques were protected and failed to demonstrate any clinical or radiographic signs of pneumonia. These studies demonstrate that a consensus MERS spike protein synthetic DNA vaccine can induce protective responses against viral challenge, indicating that this strategy may have value as a possible vaccine modality against this emerging pathogen.

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Section: Discussionmentioning

confidence: 99%

A synthetic consensus anti–spike protein DNA vaccine induces protective immunity against Middle East respiratory syndrome coronavirus in nonhuman primates

et al. 2015

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“…The clinical efficacy of anti-DPP4 monoclonal antibodies and adenosine deaminase analogues remains uncertain because expression of catalytically inactive DPP4 still allows for MERS-CoV infection in vitro (226). Furthermore, the risk of physiological disturbances, immunopathology, and T-cell suppression should be assessed in animal studies given the wide distribution of DPP4 in different human cell types and its multiple essential metabolic and immunological functions (227,228). Alternatively, inhibitors of host cellular proteases, including furin, TMPRSS2, and cathepsins, which affect virus entry into host cells, may be considered.…”

Section: Clinical Management and Antiviralsmentioning

confidence: 99%

Middle East Respiratory Syndrome Coronavirus: Another Zoonotic Betacoronavirus Causing SARS-Like Disease

et al. 2015

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SUMMARY The source of the severe acute respiratory syndrome (SARS) epidemic was traced to wildlife market civets and ultimately to bats. Subsequent hunting for novel coronaviruses (CoVs) led to the discovery of two additional human and over 40 animal CoVs, including the prototype lineage C betacoronaviruses, Tylonycteris bat CoV HKU4 and Pipistrellus bat CoV HKU5; these are phylogenetically closely related to the Middle East respiratory syndrome (MERS) CoV, which has affected more than 1,000 patients with over 35% fatality since its emergence in 2012. All primary cases of MERS are epidemiologically linked to the Middle East. Some of these patients had contacted camels which shed virus and/or had positive serology. Most secondary cases are related to health care-associated clusters. The disease is especially severe in elderly men with comorbidities. Clinical severity may be related to MERS-CoV's ability to infect a broad range of cells with DPP4 expression, evade the host innate immune response, and induce cytokine dysregulation. Reverse transcription-PCR on respiratory and/or extrapulmonary specimens rapidly establishes diagnosis. Supportive treatment with extracorporeal membrane oxygenation and dialysis is often required in patients with organ failure. Antivirals with potent in vitro activities include neutralizing monoclonal antibodies, antiviral peptides, interferons, mycophenolic acid, and lopinavir. They should be evaluated in suitable animal models before clinical trials. Developing an effective camel MERS-CoV vaccine and implementing appropriate infection control measures may control the continuing epidemic.

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“…We recognize that these findings, together with the absence of viremia, as reported by the authors, and the lack of even a single case fatality in DCs, indicate that DCs may not only be a useful animal model for evaluating candidate vaccines and drugs against MERS but also a good reservoir of MERS-CoV. However, this form of transmission cannot yet be ascertained to implicate DCs as a significant reservoir species in the epidemiology of MERS-CoV, as noted by Nishiura et al (9). These authors stated that two conditions should be objectively examined to confirm that an animal species constitutes a reservoir: (i) the reservoir is sufficient to maintain the disease by frequently transmitting the virus to another host, and (ii) the presence of the reservoir is essential for the continuous transmission of infection.…”

Section: Lettermentioning

confidence: 67%

Concerns about Misinterpretation of Recent Scientific Data Implicating Dromedary Camels in Epidemiology of Middle East Respiratory Syndrome (MERS)

Samara

Abdoun

2014

mBio

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DPP4-directed therapeutic strategies for MERS-CoV

Cited by 29 publications

References 5 publications

A synthetic consensus anti–spike protein DNA vaccine induces protective immunity against Middle East respiratory syndrome coronavirus in nonhuman primates

A synthetic consensus anti–spike protein DNA vaccine induces protective immunity against Middle East respiratory syndrome coronavirus in nonhuman primates

Middle East Respiratory Syndrome Coronavirus: Another Zoonotic Betacoronavirus Causing SARS-Like Disease

Concerns about Misinterpretation of Recent Scientific Data Implicating Dromedary Camels in Epidemiology of Middle East Respiratory Syndrome (MERS)

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