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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Cunha-Santos, Catarina Figueira, Tiago N. Borrego, Pedro Oliveira, Soraia S. Rocha, Cheila Couto, Andreia Cantante, Cátia Santos-Costa, Quirina Azevedo-Pereira, José M. Fontes, Carlos M. G. A. Taveira, Nuno Aires-Da-Silva, Frederico Castanho, Miguel A. R. B. Veiga, Ana Salomé Goncalves, Joao |
| Description | Country affiliation: Portugal Author Affiliation: Cunha-Santos C ( aResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy bInstituto de Medicina Molecular, School of Medicine, Universidade de Lisboa, Lisboa cISCSEM-Centro de Investigação Interdisciplinar Egas Moniz, Instituto Superior de Ciências da Saúde Egas Moniz, Monte de Caparica dCIISA-Interdisciplinary Centre of Research in Animal Health, Faculdade de Medicina Veterinária, Universidade de Lisboa, Lisboa eTechnophage, Lisboa, Portugal.) |
| Abstract | OBJECTIVE: To develop a novel and potent fusion inhibitor of HIV infection based on a rational strategy for synthetic antibody library construction. DESIGN: The reduced molecular weight of single-domain antibodies (sdAbs) allows targeting of cryptic epitopes, the most conserved and critical ones in the context of HIV entry. Heavy-chain sdAbs from camelids are particularly suited for this type of epitope recognition because of the presence of long and flexible antigen-binding regions [complementary-determining regions (CDRs)]. METHODS: We translated camelid CDR features to a rabbit light-chain variable domain (VL) and constructed a library of minimal antibody fragments with elongated CDRs. Additionally to elongation, CDRs' variability was restricted to binding favorable amino acids to potentiate the selection of high-affinity sdAbs. The synthetic library was screened against a conserved, hidden, and crucial-to-fusion sequence on the heptad-repeat 1 (HR1) region of the HIV-1 envelope glycoprotein. RESULTS: Two anti-HR1 VLs, named F63 and D104, strongly inhibited laboratory-adapted HIV-1 infectivity. F63 also inhibited infectivity of HIV-1 and HIV-2 primary isolates similarly to the Food and Drug Administration-approved fusion inhibitor T-20 and HIV-1 strains resistant to T-20. Moreover, epitope mapping of F63 revealed a novel target sequence within the highly conserved hydrophobic pocket of HR1. F63 was also capable of interacting with viral and cell lipid membrane models, a property previously associated with T-20's inhibitory mechanism. CONCLUSION: In summary, to our best knowledge, we developed the first potent and broad VL sdAb fusion inhibitor of HIV infection. Our study also gives insights into engineering strategies that could be explored to enhance the development of antiviral drugs. |
| File Format | HTM / HTML |
| ISSN | 02699370 |
| Issue Number | 11 |
| Journal | AIDS |
| Volume Number | 30 |
| e-ISSN | 14735571 |
| Language | English |
| Publisher | Lippincott Williams & Wilkins |
| Publisher Date | 2016-07-17 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | One Nation One Subscription (ONOS) |
| Content Type | Text |
| Resource Type | Article |
| Subject | Infectious Diseases Immunology and Allergy Immunology |
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