Un ataque combinado químico, virológico, biofísico y estructural hace posible la obtención de nuevos inhibidores de entrada celular de SARS-CoV-2 y la caracterización de su mecanismo de inhibición

Resumen del trabajo presentado al 45º Congreso de la Sociedad Española de Bioquímica y Biología Molecular (SEBBM), celebrado en Zaragoza del 5 al 8 de septiembre de 2023.IBV-COVID19 Pipeline: C.Espinosa, N.Gougeard, M.P.Hernández-Sierra, A.Rubio-del-Campo, R.Ruiz-Partida, L.Villamayor.El virus SARS-CoV-2 causa el COVID-19 al infectar las células a través de la interacción de la proteína de su espícula (S) con el receptor celular enzima convertidora de angiotensina 2 (ACE2). Para buscar inhibidores de este paso clave en la infección viral, examinamos una biblioteca interna (IQM-CSIC, Madrid) de compuestos multivalentes derivados de triptófano, primero usando pseudopartículas de Virus de Estomatits Vesicular que expresaban S (I2SysBio, UV y CSIC, Valencia), identificando un compuesto como potente inhibidor de entrada no citotóxico. La optimización química (IQM-CSIC) generó otros dos potentes inhibidores de entrada no citotóxicos que, como 2, también inhibieron la entrada celular de SARS-CoV-2 genuino (I2SysBio). Los estudios con proteínas recombinantes puras (IBV-CSIC, Valencia) usando termofluor y termoforesis de microescala revelaron la unión de estos compuestos a S, y a su dominio de unión al receptor producido separadamente, probando interferencia con la interacción con ACE2. La criomicroscopía electrónica de S (IBV-CSIC), libre o unido al compuesto activo, arrojó luz sobre los mecanismos de inhibición por estos compuestos de la entrada viral a la célula. Esta actividad triinstitucional combinada ha identificado y caracterizado una nueva clase de inhibidores de entrada de SARS-CoV-2 de claro potencial preventivo o terapéutico de COVID-19.ECNextGeneration EUfund 2020/2094 de CSIC/PTI Salud Global; Crue/CSIC/Santander Fondo Supera Covid-19;CSIC-COV19-082; CIBERER-ISCIIICOV20/00437; Covid19-SCI/GValenciana (RG);PID2020- 120322RB-C21 (VR) y PID2020-116880GB-I00 (JLLl) Agenc. Estat Investig.Peer reviewe

Trimères et tétramères de tryptophane C2-thioéther pour traiter des infections par bêtacoronoavirus

[EN] The present invention relates to C2-thioether tryptophan (Trp) trimers and tetramers in which differently substituted thio aryl rings have been introduced at the C2 position of the indole ring of each T rp moiety. The invention also refers to their therapeutic use for the treatment or prevention of betacoronoavirus infections, mainly against SARS- CoV-2 infection.[FR] La présente invention concerne des trimères et des tétramères de tryptophane C2-thioéther (Trp), des cycles thio-aryle substitués différemment ayant été introduits en position C2 du cycle indole de chaque fragment Trp. L'invention concerne également leur utilisation thérapeutique pour le traitement ou la prévention d'infections par bêtacoronoavirus, principalement contre une infection par le SARS-CoV-2.Peer reviewedConsejo Superior de Investigaciones Científicas, Universitat de ValènciaA1 Solicitud de patente con informe sobre el estado de la técnic

Trimères et tétramères de tryptophane C2-thioéther pour traiter des infections par bêtacoronoavirus

The present invention relates to C2-thioether tryptophan (Trp) trimers and tetramers in which differently substituted thio aryl rings have been introduced at the C2 position of the indole ring of each Trp moiety. The invention also refers to their therapeutic use for the treatment or prevention of betacoronoavirus infections, mainly against SARS-CoV-2 infection.Peer reviewedConsejo Superior de Investigaciones Científicas, Universitat de ValènciaA1 Solicitud de patente con informe sobre el estado de la técnic

Tryptophan trimers efficiently inhibit SARS-CoV-2 entry into the host cells

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Tryptophan trimers and tetramers inhibit dengue and Zika virus replication by interfering with viral attachment processes

Here, we report a class of tryptophan trimers and tetramers that inhibit (at low micromolar range) dengue and Zika virus infection in vitro. These compounds (AL family) have three or four peripheral tryptophan moieties directly linked to a central scaffold through their amino groups; thus, their carboxylic acid groups are free and exposed to the periphery. Structure-activity relationship (SAR) studies demonstrated that the presence of extra phenyl rings with substituents other than COOH at the N1 or C2 position of the indole side chain is a requisite for the antiviral activity against both viruses. The molecules showed potent antiviral activity, with low cytotoxicity, when evaluated on different cell lines. Moreover, they were active against laboratory and clinical strains of all four serotypes of dengue virus as well as a selected group of Zika virus strains. Additional mechanistic studies performed with the two most potent compounds (AL439 and AL440) demonstrated an interaction with the viral envelope glycoprotein (domain III) of dengue 2 virus, preventing virus attachment to the host cell membrane. Since no antiviral agent is approved at the moment against these two flaviviruses, further pharmacokinetic studies with these molecules are needed for their development as future therapeutic/prophylactic drugs.This work was supported by KU Leuven and the Fonds Wetenschappelijk Onder-zoek (FWO grant PF/10/018), the Spanish MINECO (projects SAF2015-64629-C2-1-Rand SAF2015-64629-C2-2-R [MINECO/FEDER]), and the Spanish Agencia EstatalConsejo Superior de Investigaciones Científicas (CSIC; projects CSIC201680E079 and201980E028). The Spanish MEC/MINECO is also acknowledged for grants to B.M.-G.and O.M.-

Scaffold Simplification Strategy Leads to a Novel Generation of Dual Human Immunodeficiency Virus and Enterovirus-A71 Entry Inhibitors

Currently, there are only three FDA-approved drugs that inhibit human immunodeficiency virus (HIV) entry-fusion into host cells. The situation is even worse for enterovirus EV71 infection for which no antiviral therapies are available. We describe here the discovery of potent entry dual inhibitors of HIV and EV71. These compounds contain in their structure three or four tryptophan (Trp) residues linked to a central scaffold. Critical for anti-HIV/EV71 activity is the presence of extra phenyl rings, bearing one or two carboxylates, at the C2 position of the indole ring of each Trp residue. The most potent derivatives, 22 and 30, inhibit early steps of the replicative cycles of HIV-1 and EV-A71 by interacting with their respective viral surfaces (glycoprotein gp120 of HIV and the fivefold axis of the EV-A71 capsid). The high potency, low toxicity, facile chemical synthesis, and great opportunities for chemical optimization make them useful prototypes for future medicinal chemistry studies.This work was supported by the Spanish Plan Nacional (Subprograma Retos) [projects SAF2015-64629-C2-1-R and SAF2015-64629-C2-2-R (MINECO/FEDER)], the Spanish “Ministerio de Ciencia, Innovación y Universidades” (project PID2019-104070RB-C21), and by the Spanish Agencia Estatal Consejo Superior de Investigaciones Cientifí cas (CSIC, Projects CSIC-PIE-201980E100 and CSIC-PIE- 201980E028), “The Centers of Excellence” of the KU Leuven (EF-05/15 and PF-10/18), EU FP7 (FP7/2007−2013) Project EUVIRNA (Grant 408 Agreement 264286), EU FP7 SILVER (Contract HEALTH-F3-2010-260644), a grant from the Belgian Interuniversity Attraction Poles (IAP) Phase VIIP7/ 45 (BELVIR), and the EU FP7 Industry-Academia Partnerships and Pathways Project AIROPICO. The Spanish MEC/MINECO is also acknowledged for grants to B.M.-G. and O.M.-M. and the China Scholarship Council (CSC) (grant 201403250056) for a grant to L.S. S.H. received a grant from the Pennsylvania Department of Health using Tobacco CURE Funds. We also thank Charlotte Vanderheydt, Sandra Claes, and Evelyne Van Kerckhove for helping with the processing of the antiviral data. This work has been awarded with the Janssen (XVIII call) and Esteve (XIX call) prizes within the “Prizes for Young Researchers of the Spanish Society of Medicinal Chemistry (SEQT).Peer reviewe