ArticleJournal of molecular biology2008
Combinatorial optimization of a CD4-mimetic miniprotein and cocrystal structures with HIV-1 gp120 envelope glycoprotein.
Article in Journal of molecular biology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 59 citations in OpenAlex.
- Cell-cell transmission enables HIV-1 to evade inhibition by potent CD4bs directed antibodies.PLoS pathogens · 2012Trial
- Computational discovery of SARS-CoV-2 viral entry inhibitory peptides fromFrontiers in bioinformatics · 2026Article
- Enhancing Sensitivity of Nuclear Magnetic Resonance in Biomolecules: Parahydrogen-Induced Hyperpolarization in Synthetic Disulfide-Rich Miniproteins.Journal of the American Chemical Society · 2024Article
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- Trapping the HIV-1 V3 loop in a helical conformation enables broad neutralization.Nature structural & molecular biology · 2023Article
- Design of human immunodeficiency virus-1 neutralizing peptides targeting CD4-binding site: An integrative computational biologics approach.Frontiers in medicine · 2022Article
- Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization.Nature communications · 2021Article
- Cryo-EM structures of HIV-1 trimer bound to CD4-mimetics BNM-III-170 and M48U1 adopt a CD4-bound open conformation.Nature communications · 2021Article
- Development of Protein- and Peptide-Based HIV Entry Inhibitors Targeting gp120 or gp41.Viruses · 2019Review
- Targeting the Late Stage of HIV-1 Entry for Antibody-Dependent Cellular Cytotoxicity: Structural Basis for Env Epitopes in the C11 Region.Structure (London, England : 1993) · 2017Article
- Cross-Linking of a CD4-Mimetic Miniprotein with HIV-1 Env gp140 Alters Kinetics and Specificities of Antibody Responses against HIV-1 Env in Macaques.Journal of virology · 2017Article
- Delineating CD4 dependency of HIV-1: Adaptation to infect low level CD4 expressing target cells widens cellular tropism but severely impacts on envelope functionality.PLoS pathogens · 2017Article
- Capacity of Broadly Neutralizing Antibodies to Inhibit HIV-1 Cell-Cell Transmission Is Strain- and Epitope-Dependent.PLoS pathogens · 2015Article
- HIV-1 gp120 as a therapeutic target: navigating a moving labyrinth.Expert opinion on therapeutic targets · 2015Review
- Thermosensitive and mucoadhesive pluronic-hydroxypropylmethylcellulose hydrogel containing the mini-CD4 M48U1 is a promising efficient barrier against HIV diffusion through macaque cervicovaginal mucus.Antimicrobial agents and chemotherapy · 2015Article
- High Proteolytic Resistance of Spider-Derived Inhibitor Cystine Knots.International journal of peptides · 2015Article
- Trimeric HIV Env provides epitope occlusion mediated by hypervariable loops.Scientific reports · 2014Article
- Crystal structures of HIV-1 gp120 envelope glycoprotein in complex with NBD analogues that target the CD4-binding site.PloS one · 2014Article
- Exceptionally potent and broadly cross-reactive, bispecific multivalent HIV-1 inhibitors based on single human CD4 and antibody domains.Journal of virology · 2014Article
- Allosteric induction of the CD4-bound conformation of HIV-1 Gp120.Retrovirology · 2013Article
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
Abstract
Miniproteins provide a bridge between proteins and small molecules. Here we adapt methods from combinatorial chemistry to optimize CD4M33, a synthetic miniprotein into which we had previously transplanted the HIV-1 gp120 binding surface of the CD4 receptor. Iterative deconvolution of generated libraries produced CD4M47, a derivative of CD4M33 that had been optimized at four positions. Surface plasmon resonance demonstrated fourfold to sixfold improvement in CD4M47 affinity for gp120 to a level about threefold tighter than that of CD4 itself. Assessment of the neutralization properties of CD4M47 against a diverse range of isolates spanning from HIV-1 to SIVcpz showed that CD4M47 retained the extraordinary breadth of the parent CD4M33, but yielded only limited improvements in neutralization potencies. Crystal structures of CD4M47 and a phenylalanine variant ([Phe23]M47) were determined at resolutions of 2.4 and 2.6 A, in ternary complexes with HIV-1 gp120 and the 17b antibody. Analysis of these structures revealed a correlation between mimetic affinity for gp120 and overall mimetic-gp120 interactive surface. A correlation was also observed between CD4- and mimetic-induced gp120 structural similarity and CD4- and mimetic-induced gp120 affinity for the CCR5 coreceptor. Despite mimetic substitutions, including a glycine-to-(d)-proline change, the gp120 conformation induced by CD4M47 was as close or closer to the conformation induced by CD4 as the one induced by the parent CD4M33. Our results demonstrate the ability of combinatorial chemistry to optimize a disulfide-containing miniprotein, and of structural biology to decipher the resultant interplay between binding affinity, neutralization breadth, molecular mimicry, and induced affinity for CCR5.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.