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1.
Eur J Med Chem ; 253: 115311, 2023 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-37043904

RESUMO

Despite the approval of vaccines, monoclonal antibodies and restrictions during the pandemic, the demand for new efficacious and safe antivirals is compelling to boost the therapeutic arsenal against the COVID-19. The viral 3-chymotrypsin-like protease (3CLpro) is an essential enzyme for replication with high homology in the active site across CoVs and variants showing an almost unique specificity for Leu-Gln as P2-P1 residues, allowing the development of broad-spectrum inhibitors. The design, synthesis, biological activity, and cocrystal structural information of newly conceived peptidomimetic covalent reversible inhibitors are herein described. The inhibitors display an aldehyde warhead, a Gln mimetic at P1 and modified P2-P3 residues. Particularly, functionalized proline residues were inserted at P2 to stabilize the ß-turn like bioactive conformation, modulating the affinity. The most potent compounds displayed low/sub-nM potency against the 3CLpro of SARS-CoV-2 and MERS-CoV and inhibited viral replication of three human CoVs, i.e. SARS-CoV-2, MERS-CoV, and HCoV 229 in different cell lines. Particularly, derivative 12 exhibited nM-low µM antiviral activity depending on the virus, and the highest selectivity index. Some compounds were co-crystallized with SARS-CoV-2 3CLpro validating our design. Altogether, these results foster future work toward broad-spectrum 3CLpro inhibitors to challenge CoVs related pandemics.


Assuntos
COVID-19 , Coronavírus da Síndrome Respiratória do Oriente Médio , Peptidomiméticos , Humanos , SARS-CoV-2 , Inibidores de Proteases/química , Peptidomiméticos/farmacologia , Peptidomiméticos/química , Raios X , Peptídeo Hidrolases , Antivirais/química
2.
EMBO Mol Med ; 15(5): e17580, 2023 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-36946379

RESUMO

Alongside vaccines, antiviral drugs are becoming an integral part of our response to the SARS-CoV-2 pandemic. Nirmatrelvir-an orally available inhibitor of the 3-chymotrypsin-like cysteine protease-has been shown to reduce the risk of progression to severe COVID-19. However, the impact of nirmatrelvir treatment on the development of SARS-CoV-2-specific adaptive immune responses is unknown. Here, by using mouse models of SARS-CoV-2 infection, we show that nirmatrelvir administration blunts the development of SARS-CoV-2-specific antibody and T cell responses. Accordingly, upon secondary challenge, nirmatrelvir-treated mice recruited significantly fewer memory T and B cells to the infected lungs and mediastinal lymph nodes, respectively. Together, the data highlight a potential negative impact of nirmatrelvir treatment with important implications for clinical management and might help explain the virological and/or symptomatic relapse after treatment completion reported in some individuals.


Assuntos
Imunidade Adaptativa , Antivirais , Tratamento Farmacológico da COVID-19 , Lactamas , Animais , Camundongos , COVID-19/imunologia , SARS-CoV-2 , Antivirais/administração & dosagem , Imunidade Adaptativa/efeitos dos fármacos , Lactamas/administração & dosagem , Células T de Memória/imunologia , Linfócitos B/imunologia , Camundongos Endogâmicos C57BL
3.
Int J Mol Sci ; 21(16)2020 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-32784899

RESUMO

The pandemic evolution of SARS-CoV-2 infection is forcing the scientific community to unprecedented efforts to explore all possible approaches against COVID-19. In this context, targeting virus entry is a promising antiviral strategy for controlling viral infections. The main strategies pursued to inhibit the viral entry are considering both the virus and the host factors involved in the process. Primarily, direct-acting antivirals rely on inhibition of the interaction between ACE2 and the receptor binding domain (RBD) of the Spike (S) protein or targeting the more conserved heptad repeats (HRs), involved in the membrane fusion process. The inhibition of host TMPRSS2 and cathepsins B/L may represent a complementary strategy to be investigated. In this review, we discuss the development entry inhibitors targeting the S protein, as well as the most promising host targeting strategies involving TMPRSS2 and CatB/L, which have been exploited so far against CoVs and other related viruses.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Inibidores de Serina Proteinase/farmacologia , Internalização do Vírus/efeitos dos fármacos , Animais , Betacoronavirus/metabolismo , Betacoronavirus/fisiologia , Humanos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismo
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