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Cell Mol Life Sci ; 78(21-22): 6735-6744, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1377320


Kallikrein-related peptidases (KLKs) or kallikreins have been linked to diverse (patho) physiological processes, such as the epidermal desquamation and inflammation, seminal clot liquefaction, neurodegeneration, and cancer. Recent mounting evidence suggests that KLKs also represent important regulators of viral infections. It is well-established that certain enveloped viruses, including influenza and coronaviruses, require proteolytic processing of their hemagglutinin or spike proteins, respectively, to infect host cells. Similarly, the capsid protein of the non-enveloped papillomavirus L1 should be proteolytically cleaved for viral uncoating. Consequently, extracellular or membrane-bound proteases of the host cells are instrumental for viral infections and represent potential targets for drug development. Here, we summarize how extracellular proteolysis mediated by the kallikreins is implicated in the process of influenza (and potentially coronavirus and papillomavirus) entry into host cells. Besides direct proteolytic activation of viruses, KLK5 and 12 promote viral entry indirectly through proteolytic cascade events, like the activation of thrombolytic enzymes that also can process hemagglutinin, while additional functions of KLKs in infection cannot be excluded. In the light of recent evidence, KLKs represent potential host targets for the development of new antivirals. Humanized animal models to validate their key functions in viral infections will be valuable.

COVID-19/enzymology , COVID-19/virology , Host Microbial Interactions/physiology , Kallikreins/metabolism , SARS-CoV-2 , Virus Diseases/enzymology , Animals , Asthma/etiology , Coronavirus/genetics , Coronavirus/pathogenicity , Coronavirus/physiology , Host Microbial Interactions/genetics , Humans , Orthomyxoviridae/genetics , Orthomyxoviridae/pathogenicity , Orthomyxoviridae/physiology , Papillomavirus Infections/enzymology , Papillomavirus Infections/virology , Picornaviridae Infections/complications , Picornaviridae Infections/enzymology , Picornaviridae Infections/virology , Protein Processing, Post-Translational , Proteolysis , Rhinovirus/pathogenicity , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Varicella Zoster Virus Infection/enzymology , Varicella Zoster Virus Infection/virology , Viral Proteins/genetics , Viral Proteins/metabolism , Virus Diseases/virology , Virus Internalization
Eur J Med Chem ; 209: 112884, 2021 Jan 01.
Article in English | MEDLINE | ID: covidwho-800277


A novel methodology to access alkynyl nucleoside analogues is elaborated. Highly fluorescent 5-alkynylfuropyrimidines were synthesized (97-46%) and their antiviral properties investigated in vitro. Regiochemistry of the functionalization was achieved with the aid of 5-endo-dig electrophilic halocyclization of acetyl 5-p-tolyl- or 5-p-pentylphenyl-2'-deoxyuridine. Structure of one of the resulting nucleosides, 6-p-tolyl-5-iodo-2'-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-one, was confirmed by X-ray crystallography, and its conformation was compared to related nucleosides. Diverse alkynyl substituents were introduced at the heterobicyclic base C-5 position via Sonogashira coupling of 5-iodo-2'-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-ones. The resulting compounds had fluorescence emissions of 452-481 nm. High quantum yields of 0.53-0.60 were observed for 9-ethynyl-9-fluorenol and propargyl alcohol/methyl ether-modified furopyrimidines. These modified nucleosides, designed in the form of ribose acetyl esters, are potential tools for fluorescent tagging, studying nucleoside metabolism, 2'-deoxyribonucleoside kinase activity, and antiviral activity. Antiviral assays against a broad spectrum of DNA and RNA viruses showed that in human embryonic lung (HEL) cell cultures some of the compounds posess antiviral activity (EC50 1.3-13.2 µM) against varicella-zoster virus (VZV). The alkynyl furopyrimidine with two p-pentylphenyl substituents emerged as the best compound with reasonable and selective anti-VZV activity, confirming p-pentylphenyl potency as a pharmacophore.

Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Pyrimidine Nucleosides/chemistry , Pyrimidine Nucleosides/pharmacology , Antiviral Agents/chemical synthesis , Cell Line , Fluorescence , Halogenation , Herpesvirus 3, Human/drug effects , Humans , Models, Molecular , Pyrimidine Nucleosides/chemical synthesis , Varicella Zoster Virus Infection/drug therapy , Varicella Zoster Virus Infection/virology