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Spiro-ß-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium

2021-01-04Journal article Restricted access
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dc.contributor.authorBártolo, Inês
dc.contributor.authorSantos, Bruna S.
dc.contributor.authorFontinha, Diana
dc.contributor.authorMachado, Marta
dc.contributor.authorFrancisco, Denise
dc.contributor.authorSepodes, Bruno
dc.contributor.authorRocha, Joao
dc.contributor.authorMota-Filipe, Hélder
dc.contributor.authorPinto, Rui
dc.contributor.authorFigueira, Maria-Eduardo
dc.contributor.authorBarroso, Helena
dc.contributor.authorNascimento, Teresa
dc.contributor.authorMatos, António P. Alves de
dc.contributor.authorAlves, Américo
dc.contributor.authorAlves, Nuno G.
dc.contributor.authorSimões, Carlos J. V.
dc.contributor.authorPrudêncio, Miguel
dc.contributor.authorMelo, Teresa M. V. D. Pinho E
dc.contributor.authorTaveira, Nuno
dc.date.accessioned2023-08-21T18:59:07Z
dc.date.available2023-08-21T18:59:07Z
dc.date.issued2021-01-04
dc.date.updated2023-02-03T12:14:40Z
dc.description.abstractThe high burden of malaria and HIV/AIDS prevents economic and social progress in developing countries. A continuing need exists for development of novel drugs and treatment regimens for both diseases in order to address the tolerability and long-term safety concerns associated with current treatment options and the emergence of drug resistance. We describe new spiro-β-lactam derivatives with potent (nM) activity against HIV and Plasmodium and no activity against bacteria and yeast. The best performing molecule of the series, BSS-730A, inhibited both HIV-1 and HIV-2 replication with an IC50 of 13 ± 9.59 nM and P. berghei hepatic infection with an IC50 of 0.55 ± 0.14 μM with a clear impact on parasite development. BSS-730A was also active against the erythrocytic stages of P. falciparum, with an estimated IC50 of 0.43 ± 0.04 μM. Time-of-addition studies showed that BSS-730A potentially affects all stages of the HIV replicative cycle, suggesting a complex mechanism of action. BSS-730A was active against multidrug-resistant HIV isolates, with a median 2.4-fold higher IC50 relative to control isolates. BSS-730A was equally active against R5 and X4 HIV isolates and displayed strong synergism with the entry inhibitor AMD3100. BSS-730A is a promising candidate for development as a potential therapeutic and/or prophylactic agent against HIV and Plasmodium.pt_PT
dc.description.sponsorshipCoimbra Chemistry Centre (CQC), University of Coimbra, Portugal, is supported by the Portuguese Agency for Scientific Research, “Fundação para a Ciência e a Tecnologia” (FCT) through Projects UIDB/00313/2020 and UIDP/00313/2020, cofunded by COMPETE2020-UE. iMed. ULisboa, Faculdade de Farmacia de Lisboa, Portugal, is supported by the Portuguese Agency for Scientific Research, “Fundação para a Ciência e a Tecnologia” (FCT) through Projects UIDB/04138/2020 and UIDP/04138/2020. FCT is also acknowledged for Project PTDC-SAU-INF-29550-2017 to M.P., for a postdoc fellowship to I.B. (SFRH/BPD/76225/2011) and for Ph.D. fellowships to N.A. (PD/BD/135287/2017) and A.A. (SFRH/BD/128910/2017). The funders had no role in study design, data collection, and interpretation, nor the decision to submit the work for publication. We acknowledge the UC1010 NMR facility for producing the NMR data (www.nmrccc.uc.pt) and Filipa Teixeira for producing Plasmodium-infected Anopheles mosquitoes for sporozoite isolation.pt_PT
dc.description.versioninfo:eu-repo/semantics/acceptedVersionpt_PT
dc.identifier.citationBártolo I, Santos BS, Fontinha D, Machado M, Francisco D, Sepodes B, et al. Spiro-β-lactam bss-730a displays potent activity against hiv and plasmodium. ACS Infect Dis [Internet]. 12 de fevereiro de 2021;7(2):421–34. Disponível em: https://pubs.acs.org/doi/10.1021/acsinfecdis.0c00768pt_PT
dc.identifier.doi10.1021/acsinfecdis.0c00768pt_PT
dc.identifier.eid2-s2.0-85099655355
dc.identifier.issn2373-8227
dc.identifier.slugcv-prod-3091876
dc.identifier.urihttp://hdl.handle.net/10451/58948
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherACS Publishingpt_PT
dc.relationPTDC-SAU-INF-29550-2017pt_PT
dc.relationCoimbra Chemistry Center
dc.relationCoimbra Chemistry Center
dc.relationResearch Institute for Medicines
dc.relationResearch Institute for Medicines
dc.relationDESENVOLVIMENTO DE NOVOS MICROBICIDAS PARA PREVENIR A INFECÇÃO POR VIH
dc.relationBroadening the spectrum of spito-B-lactams antiviral activity: from new targets identification to the discovery of new compounds with anti-influenza activity.
dc.relationNovel spiro-lactams as new antimicrobial agents
dc.relation.publisherversionhttps://pubs.acs.org/doi/10.1021/acsinfecdis.0c00768#pt_PT
dc.subjectAIDSpt_PT
dc.subjectmalariapt_PT
dc.subjectspiro-β-lactamspt_PT
dc.subjectBSS-730Apt_PT
dc.subjectanti-HIV activitypt_PT
dc.subjectantiplasmodial activitypt_PT
dc.titleSpiro-ß-lactam BSS-730A Displays Potent Activity against HIV and Plasmodiumpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCoimbra Chemistry Center
oaire.awardTitleCoimbra Chemistry Center
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleDESENVOLVIMENTO DE NOVOS MICROBICIDAS PARA PREVENIR A INFECÇÃO POR VIH
oaire.awardTitleBroadening the spectrum of spito-B-lactams antiviral activity: from new targets identification to the discovery of new compounds with anti-influenza activity.
oaire.awardTitleNovel spiro-lactams as new antimicrobial agents
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00313%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F00313%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F76225%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F135287%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F128910%2F2017/PT
oaire.citation.endPage434pt_PT
oaire.citation.issue2pt_PT
oaire.citation.startPage421pt_PT
oaire.citation.titleACS Infectious Diseasespt_PT
oaire.citation.volume7pt_PT
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