ArticleProceedings of the National Academy of Sciences of the United States of America2004
Medicinal chemistry applied to a synthetic protein: development of highly potent HIV entry inhibitors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 159 citations in OpenAlex.
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- Current status and trends in small nucleic acid drug development: Leading the future.Acta pharmaceutica Sinica. B · 2024Review
- Arylsulfatases and neuraminidases modulate engagement of CCR5 by chemokines by removing key electrostatic interactions.Scientific reports · 2024Article
- Descriptive molecular pharmacology of the δ opioid receptor (DOR): A computational study with structural approach.PloS one · 2024Article
- Bioorthogonal Tethering Enhances Drug Fragment Affinity for G Protein-Coupled Receptors in Live Cells.Journal of the American Chemical Society · 2023Article
- Co-receptor signaling in the pathogenesis of neuroHIV.Retrovirology · 2021Review
- Purinergic Receptors Crosstalk with CCR5 to Amplify CaCellular and molecular neurobiology · 2021Article
- Structural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist.Science advances · 2021Article
- Modification of N-terminal α-amine of proteins via biomimetic ortho-quinone-mediated oxidation.Nature communications · 2021Article
- Unmapped exome reads implicate a role for Anelloviridae in childhood HIV-1 long-term non-progression.NPJ genomic medicine · 2021Article
- General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins.Nature communications · 2021Article
- Perspective: Implications of Ligand-Receptor Binding Kinetics for Therapeutic Targeting of G Protein-Coupled Receptors.ACS pharmacology & translational science · 2020Review
- Selective Allosteric Modulation of N-Terminally Cleaved, but Not Full Length CCL3 in CCR1.ACS pharmacology & translational science · 2019Article
- High-Affinity Binding of Chemokine Analogs that Display Ligand Bias at the HIV-1 Coreceptor CCR5.Biophysical journal · 2019Article
- Novel protein science enabled by total chemical synthesis.Protein science : a publication of the Protein Society · 2019Review
- HIV Entry and Its Inhibition by Bifunctional Antiviral Proteins.Molecular therapy. Nucleic acids · 2018Review
- Genetic Strategies for HIV Treatment and Prevention.Molecular therapy. Nucleic acids · 2018Review
- Rapid and low-cost multiplex synthesis of chemokine analogs.The Journal of biological chemistry · 2018Article
- Pharmacokinetics of the Protein Microbicide 5P12-RANTES in Sheep following Single-Dose Vaginal Gel Administration.Antimicrobial agents and chemotherapy · 2017Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 1 institution in 1 country.
Funding
Abstract
We have used total chemical synthesis to perform high-resolution dissection of the pharmacophore of a potent anti-HIV protein, the aminooxypentane oxime of [glyoxylyl1]RANTES(2-68), known as AOP-RANTES, of which we designed and made 37 analogs. All involved incorporation of one or more rationally chosen nonnatural noncoded structures, for which we found a clear comparative advantage over coded ones. We investigated structure-activity relationships in the pharmacophore by screening the analogs for their ability to block the HIV entry process and produced a derivative, PSC-RANTES [N-nonanoyl, des-Ser1[L-thioproline2, L-cyclohexylglycine3]-RANTES(2-68)], which is 50 times more potent than AOP-RANTES. This promising group of compounds might be optimized yet further as potential prophylactic and therapeutic anti-HIV agents. The remarkable potency of our RANTES analogs probably involves the unusual mechanism of intracellular sequestration of CC-chemokine receptor 5 (CCR5), and it has been suggested that this arises from enhanced affinity for the receptor. We found that inhibitory potency and capacity to induce CCR5 down-modulation do appear to be correlated, but that unexpectedly, inhibitory potency and affinity for CCR5 do not. We believe this study represents the proof of principle for the use of a medicinal chemistry approach, above all one showing the advantage of noncoded structures, to the optimization of the pharmacological properties of a protein. Medicinal chemistry of small molecules is the foundation of modern pharmaceutical practice, and we believe we have shown that techniques have now reached the point at which the approach could also be applied to the many macromolecular drugs now in common use.
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Registered trials
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.