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1.
Virus Res ; 342: 199330, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38272241

RESUMEN

The Middle East respiratory syndrome (MERS) is a severe respiratory disease with high fatality rates, caused by the Middle East respiratory syndrome coronavirus (MERS-CoV). The virus initiates infection by binding to the CD26 receptor (also known as dipeptidyl peptidase 4 or DPP4) via its spike protein. Although the receptor-binding domain (RBD) of the viral spike protein and the complex between RBD and the extracellular domain of CD26 have been studied using X-ray crystallography, conflicting studies exist regarding the importance of certain amino acids outside the resolved RBD-CD26 complex interaction interface. To gain atomic-level knowledge of the RBD-CD26 complex, we employed computational simulations to study the complex's dynamic behavior as it evolves from its crystal structure to a conformation stable in solution. Our study revealed previously unidentified interaction regions and interacting amino acids within the complex, determined a novel comprehensive RBD-binding domain of CD26, and by that expanded the current understanding of its structure. Additionally, we examined the impact of a single amino acid substitution, E513A, on the complex's stability. We discovered that this substitution disrupts the complex through an allosteric domino-like mechanism that affects other residues. Since MERS-CoV is a zoonotic virus, we evaluated its potential risk of human infection via animals, and suggest a low likelihood for possible infection by cats or dogs. The molecular structural information gleaned from our insights into the RBD-CD26 complex pre-dissociative states may be proved useful not only from a mechanistic view but also in assessing inter-species transmission and in developing anti-MERS-CoV antiviral therapeutics.


Asunto(s)
Infecciones por Coronavirus , Coronavirus del Síndrome Respiratorio de Oriente Medio , Humanos , Animales , Perros , Dipeptidil Peptidasa 4/genética , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Glicoproteína de la Espiga del Coronavirus/genética , Aminoácidos
2.
Mol Immunol ; 145: 3-16, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35272105

RESUMEN

In the early 1960's the first human coronaviruses (designated 229E and OC43) were identified as etiologic agents of the common cold, to be followed by the subsequent isolation of three more human coronaviruses similarly associated with cold-like diseases. In contrast to these "mild" coronaviruses, over the last 20 years there have been three independent events of emergence of pandemic severe and acute life-threatening respiratory diseases caused by three novel beta-coronaviruses, SARS CoV, MERS CoV and most recently SARS CoV2. Whereas the first SARS CoV appeared in November 2002 and spontaneously disappeared by the summer of 2003, MERS CoV has continued persistently to spill over to humans via an intermediary camel vector, causing tens of cases annually. Although human-to-human transmission is rare, the fatality rate of MERS CoV disease is remarkably higher than 30%. COVID-19 however, is fortunately much less fatal, despite that its etiologic agent, SARS CoV2, is tremendously infectious, particularly with the recent evolution of the Omicron variants of concern (BA.1 and BA.2). Of note, MERS CoV prevalence in camel populations in Africa and the Middle East is extremely high. Moreover, MERS CoV and SARS CoV2 co-exist in the Middle East and especially in Saudi Arabia and the UAE, where sporadic incidences of co-infection have already been reported. Co-infection, either due to reverse spill-over of SARS CoV2 to camels or in double infected humans could lead to recombination between the two viruses, rendering either SARS CoV2 more lethal or MERS CoV more transmittable. In an attempt to prepare for what could develop into a catastrophic event, we have focused on developing a novel epitope-based immunogen for MERS CoV. Implementing combinatorial phage-display conformer libraries, the Receptor Binding Motif (RBM) of the MERS CoV Spike protein has been successfully reconstituted and shown to be recognized by a panel of seven neutralizing monoclonal antibodies.


Asunto(s)
COVID-19 , Coinfección , Coronavirus del Síndrome Respiratorio de Oriente Medio , Humanos , SARS-CoV-2
3.
Biochem Pharmacol ; 182: 114206, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32828805

RESUMEN

The Toll-like receptor 7 (TLR7) agonist imiquimod is an antitumor and antiviral drug used for the treatment of skin indications such as basal cell carcinoma, squamous cell carcinoma, and genital warts caused by the human papilloma virus. We show that imiquimod has TLR7-independent activity in which it directly inhibits phosphodiesterase (PDE), leading to cAMP increase, PKA-mediated CREB phosphorylation and subsequent CRE-dependent reporter transcription. The activation of the cAMP pathway by imiquimod is synergistically amplified by the ß-adrenergic receptor agonist, isoproterenol. PDE inhibition is implied from cAMP measurements and CRE-reporter assays in intact RAW264.7 macrophages and HEK293T cells, and also directly demonstrated in-vitro using macrophages lysate. Moreover, molecular docking simulated the binding of imiquimod in the active site of PDE4B, enabled by the high molecular similarity between imiquimod and the adenine moiety of cAMP. As expected from the known anti-inflammatory role of cAMP inducers in stimulated macrophages, PDE inhibition by imiquimod results in reduced expression of the key pro-inflammatory cytokine TNFα, and enhanced expression of the key anti-inflammatory cytokine IL-10, compared to a different TLR7 agonist, loxoribine, as well as to the TLR4 agonist LPS. To conclude, our results indicate that the widely used inflammatory drug, imiquimod, is not only a TLR7 agonist, but also harbors a novel anti-inflammatory function as a PDE inhibitor. This off-target affects the desired therapeutic inflammatory activity of imiquimod and may be accountable for adverse side effects.


Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Imiquimod/farmacología , Mediadores de Inflamación/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa/farmacología , Receptor Toll-Like 7/agonistas , 3',5'-AMP Cíclico Fosfodiesterasas/metabolismo , Adyuvantes Inmunológicos/farmacología , Animales , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Mediadores de Inflamación/metabolismo , Ratones , Células RAW 264.7 , Receptor Toll-Like 7/metabolismo
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