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High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-ß-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients

2022-11-18Artigo científico Acesso aberto
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dc.contributor.authorBártolo, Inês
dc.contributor.authorMoranguinho, Inês
dc.contributor.authorGonçalves, Paloma
dc.contributor.authorAna Rita Diniz
dc.contributor.authorBorrego, Pedro
dc.contributor.authorMartin, Francisco
dc.contributor.authorFigueiredo, Inês
dc.contributor.authorGomes, Perpetua
dc.contributor.authorGonçalves, Maria Fátima
dc.contributor.authorAlves, Américo
dc.contributor.authorAlves, Nuno
dc.contributor.authorCaixas, Umbelina
dc.contributor.authorVaz-Pinto, Inês
dc.contributor.authorBarahona, Isabel
dc.contributor.authorMelo, Teresa M. V. D. Pinho E
dc.contributor.authorTaveira, Nuno
dc.date.accessioned2023-08-21T14:34:05Z
dc.date.available2023-08-21T14:34:05Z
dc.date.issued2022-11-18
dc.date.updated2023-02-03T12:06:33Z
dc.description.abstractIntegrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical efficacy of raltegravir and dolutegravir is well established, the clinical efficacy of bictegravir for treating HIV-2 infected patients has not been determined. Little information is available regarding the activity of bictegravir against HIV-2 isolates from patients failing raltegravir-based therapy. In this study, we examined the phenotypic and matched genotypic susceptibility of HIV-2 primary isolates from raltegravir-naïve and raltegravir-failing patients to raltegravir, dolutegravir, and bictegravir, and to the new spiro-β-lactam BSS-730A. The instantaneous inhibitory potential (IIP) was calculated to help predict the clinical activity of bictegravir and BSS-730A. Isolates from raltegravir-naïve patients were highly sensitive to all INIs and BSS-730A. Combined integrase mutations E92A and Q148K conferred high-level resistance to raltegravir, and E92Q and T97A conferred resistance to raltegravir and dolutegravir. The antiviral activity of bictegravir and BSS-730A was not affected by these mutations. BSS-730A displayed strong antiviral synergism with raltegravir. Mean IIP values at Cmax were similar for all INIs and were not significantly affected by resistance mutations. IIP values were significantly higher for BSS-730A than for INIs. The high IIP values of bictegravir and BSS-730A for raltegravir-naïve and raltegravir-resistant HIV-2 isolates highlight their potential value for treating HIV-2 infection. Overall, the results are consistent with the high clinical efficacy of raltegravir and dolutegravir for HIV-2 infection and suggest a promising clinical profile for bictegravir and BSS-730A.pt_PT
dc.description.sponsorshipThis work was supported by Fundação para a Ciência e Tecnologia (FCT), Portugal, Aga Khan Development Network (AKDN)–Portugal Collaborative Research Network in Portuguese-speaking countries in Africa (project 332821690). CQC is supported by FCT through projects UIDB/00313/2020 and UIDP/QUI/00313/2020, co-funded by COMPETE2020-UE. iMed.ULisboa, Faculdade de Farmácia da Universidade de Lisboa, Portugal, is supported by FCT through projects UIDB/04138/2020 and UIDP/04138/2020. Inês Bártolo is supported by FCT through Norma Transitória–DL57/2016/CP1376/CT0012. Ana Rita Diniz (SFRH/BD/89140/2012), Francisco Martin (SFRH/BD/87488/2012), Inês Moranguinho (SFRH/BD/131062/2017), and Américo Alves (SFRH/BD/128910/2017) were supported by Ph.D. grants from FCT, Portugal.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationBártolo I, Moranguinho I, Gonçalves P, Diniz AR, Borrego P, Martin F, et al. High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-β-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients. International Journal of Molecular Sciences [Internet]. 2022 Nov 18;23(22):14300. Available from: http://dx.doi.org/10.3390/ijms232214300pt_PT
dc.identifier.doi10.3390/ijms232214300pt_PT
dc.identifier.slugcv-prod-3091866
dc.identifier.urihttp://hdl.handle.net/10451/58943
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationUIDP/QUI/00313/2020pt_PT
dc.relationCoimbra Chemistry Center
dc.relationResearch Institute for Medicines
dc.relationResearch Institute for Medicines
dc.relationDEVELOPMENT AND PRE-CLINICAL EVALUATION OF A NEW MICROBICIDE GEL FOR THE PREVENTION OF HIV-1 AND HIV-2 INFECTION
dc.relationHIV EPIDEMIOLOGY AND PATHOGENESIS IN WOMEN AND CHILDREN IN LUANDA, ANGOLA
dc.relationGene therapy for HIV cure using RNA replicons.
dc.relationNovel spiro-lactams as new antimicrobial agents
dc.relation.publisherversionhttps://www.mdpi.com/1422-0067/23/22/14300pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectHIV-2pt_PT
dc.subjectantiretroviral activitypt_PT
dc.subjectintegrase inhibitors (INIs)pt_PT
dc.subjectspiro-β-lactam BSS-730Apt_PT
dc.subjectinstantaneous inhibitory potential (IIP)pt_PT
dc.subjectdrug resistancept_PT
dc.titleHigh Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-ß-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patientspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCoimbra Chemistry Center
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleDEVELOPMENT AND PRE-CLINICAL EVALUATION OF A NEW MICROBICIDE GEL FOR THE PREVENTION OF HIV-1 AND HIV-2 INFECTION
oaire.awardTitleHIV EPIDEMIOLOGY AND PATHOGENESIS IN WOMEN AND CHILDREN IN LUANDA, ANGOLA
oaire.awardTitleGene therapy for HIV cure using RNA replicons.
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/UIDB%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04138%2F2020/PT
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oaire.citation.issue22pt_PT
oaire.citation.startPage14300pt_PT
oaire.citation.titleInternational Journal of Molecular Sciencespt_PT
oaire.citation.volume23pt_PT
oaire.fundingStream6817 - DCRRNI ID
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