Peptide mimotopes selected with HIV‐1‐blocking monoclonal antibodies against CCR5 represent motifs specific for HIV‐1 entry

Königs, Christoph; Pustowka, Anette; Irving, James A.; Kessel, Christoph; Klich, Katharina; Wegner, Valerie; Rowley, Merrill J.; Mackay, Ian R.; Kreuz, W.; Griesinger, Christian; Dietrich, Ursula

doi:10.1038/sj.icb.7100077

Cited by 8 publications

(5 citation statements)

References 39 publications

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“…Previous studies defined the amino acid residues on CCR5 that alter HIV-1 susceptibility, antagonist binding, and natural ligand binding (16–18, 20, 21). Based on these findings, CCR5 mutants were tested for coreceptor function using CCR5-tropic JR-FL- and ADA-pseudotyped HIV-1 luciferase reporter viruses.…”

Section: Resultsmentioning

confidence: 99%

Staphylococcus aureus Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5

Tam

Schultz

Reyes‐Robles

et al. 2016

mBio

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Leukocidin ED (LukED) is a bicomponent pore-forming toxin produced by Staphylococcus aureus that lyses host cells by targeting the chemokine receptors CC chemokine receptor type 5 (CCR5), CXCR1, CXCR2, and DARC. In addition to its role as a receptor for LukED, CCR5 is the major coreceptor for primary isolates of human immunodeficiency virus type 1 (HIV-1) and has been extensively studied. To compare how LukED and HIV-1 target CCR5, we analyzed their respective abilities to use CCR5/CCR2b chimeras to mediate cytotoxicity and virus entry. These analyses showed that the second and third extracellular loops (ECL) of CCR5 are necessary and sufficient for LukED to target the receptor and promote cell lysis. In contrast, the second ECL of CCR5 is necessary but not sufficient for HIV-1 infectivity. The analysis of CCR5 point mutations showed that glycine-163 is critical for HIV-1 infectivity, while arginine-274 and aspartic acid-276 are critical for LukED cytotoxicity. Point mutations in ECL2 diminished both HIV-1 infectivity and LukED cytotoxicity. Treatment of cells with LukED did not interfere with CCR5-tropic HIV-1 infectivity, demonstrating that LukED and the viral envelope glycoprotein use nonoverlapping sites on CCR5. Analysis of point mutations in LukE showed that amino acids 64 to 69 in the rim domain are required for CCR5 targeting and cytotoxicity. Taking the results together, this study identified the molecular basis by which LukED targets CCR5, highlighting the divergent molecular interactions evolved by HIV-1 and LukED to interact with CCR5.

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Section: Resultsmentioning

confidence: 99%

Staphylococcus aureus Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5

Tam

Schultz

Reyes‐Robles

et al. 2016

mBio

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“…Small peptides are surprisingly amenable to diverse applications, including mapping interacting epitopes (55), identifying novel drug targets (34,39), confirming the functional significance of protein-protein interactions in complex biological systems (58,61), and generating vaccines (38) and novel diagnostics (7,32,58,61). Since the surface that modulates protein-protein interaction is relatively small, competitive disruption by a blocking peptide is both feasible and therapeutically attractive (63).…”

Section: What Is a Blocking Peptide?mentioning

confidence: 94%

Blocking peptides and molecular mimicry as treatment for kidney disease

Havasi

Cohen

et al. 2017

American Journal of Physiology-Renal Physiology

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Protein mimotopes, or blocking peptides, are small therapeutic peptides that prevent protein-protein interactions by selectively mimicking a native binding domain. Inexpensive technology facilitates straightforward design and production of blocking peptides in sufficient quantities to allow preventive and therapeutic trials in both in vitro and in vivo experimental disease models. The kidney is an ideal peptide target, since small molecules undergo rapid filtration and efficient bulk absorption by tubular epithelial cells. Because the half-life of peptides is markedly prolonged in the kidneys compared with the bloodstream, blocking peptides are an attractive tool for treating diverse renal diseases, including ischemia, proteinuric states, such as membranous nephropathy and focal and segmental glomerulosclerosis, and renal cell carcinoma. Therapeutic peptides represent one of the fastest-growing reagent classes for novel drug development in human disease, partly because of their ease of administration, high binding affinity, and minimal off-target effects. This review introduces the concepts of blocking peptide design, production, and administration and highlights the potential use of therapeutic peptides to prevent or treat specific renal diseases.

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“…1C) (3). Interestingly, some peptide sequences contained additional amino acid motifs present in extracellular loops 1 and 3 of CCR5, which were previously described to be present in the mimotopes that we selected with two HIV-neutralizing MAbs against CCR5 (MAbs 3A9 and 5C7) and to be involved in HIV-1 entry (33,34,42). Due to its high reactivity, frequent selection, and strong sequence similarity to different extracellular regions of coreceptors, phage a was further analyzed.…”

Section: Resultsmentioning

confidence: 99%

“…These peptides contain amino acid motifs at the N terminus and the first and third extracellular domains of CCR5 and mimic the conformational epitopes involved in HIV-1 entry (Fig. 1C, 3A9/5C7 mimotope) (3,33,42).…”

Section: Discussionmentioning

confidence: 99%

Peptide Ligands Selected with CD4-Induced Epitopes on Native Dualtropic HIV-1 Envelope Proteins Mimic Extracellular Coreceptor Domains and Bind to HIV-1 gp120 Independently of Coreceptor Usage

Dervillez

Klaukien

Dürr

et al. 2010

J Virol

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During HIV-1 entry, binding of the viral envelope glycoprotein gp120 to the cellular CD4 receptor triggers conformational changes resulting in exposure of new epitopes, the highly conserved CD4-induced (CD4i) epitopes that are essential for subsequent binding to chemokine receptor CCR5 or CXCR4. Due to their functional conservation, CD4i epitopes represent attractive viral targets for HIV-1 entry inhibition. The aim of the present study was to select peptide ligands for CD4i epitopes on native dualtropic (R5X4) HIV-1 envelope (Env) glycoproteins by phage display. Using CD4-activated retroviral particles carrying Env from the R5X4 HIV-1 89.6 strain as the target, we performed screenings of random peptide phage libraries under stringent selection conditions. Selected peptides showed partial identity with amino acids in the extracellular domains of CCR5/CXCR4, including motifs rich in tyrosines and aspartates at the N terminus known to be important for gp120 binding. A synthetic peptide derivative (XD3) corresponding to the most frequently selected phages was optimized for Env binding on peptide arrays. Interestingly, the optimized peptide could bind specifically to gp120 derived from HIV-1 strains with different coreceptor usage, competed with binding of CD4i-specific monoclonal antibody (MAb) 17b, and interfered with entry of both a CCR5 (R5)-tropic and a CXCR4 (X4)-tropic Env pseudotyped virus. This peptide ligand therefore points at unique properties of CD4i epitopes shared by gp120 with different coreceptor usage and could thus serve to provide new insight into the conserved structural details essential for coreceptor binding for further drug development.HIV-1 entry (reviewed in reference 2) is a multistep process initiated by binding of the outer envelope (Env) glycoprotein gp120 to the CD4 receptor. This results in conformational changes leading to exposure of CD4-induced (CD4i) epitopes for the subsequent obligatory interaction with the chemokine receptor CCR5 or CXCR4. Further conformational changes in gp120 activate the fusion peptide at the N terminus of the transmembrane glycoprotein gp41 and lead to the assembly of a six-helix bundle structure that triggers membrane fusion and internalization of the viral particles. This sequential HIV-1 entry process allows the virus to protect the functionally important and highly conserved Env entry epitopes by limiting their exposure to antibodies which may neutralize the infection (35). The complex HIV-1 entry process offers the opportunity for therapeutic intervention at multiple steps. Thus, the first HIV-1 entry inhibitor approved by the FDA (T20, enfuvirtide [Fuzeon]) is a peptide inhibiting the very last step of entry, i.e., membrane fusion, by interfering with the six-helix bundle formation (39). A second entry inhibitor (maraviroc [Selzentry]), targeting CCR5, was approved by the FDA in 2007 (46). This drug, like others whose development had to be discontinued due to liver toxicities, is a CCR5 antagonist, and its use is restricted to drug-experienced HIV-1...

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Peptide mimotopes selected with HIV‐1‐blocking monoclonal antibodies against CCR5 represent motifs specific for HIV‐1 entry

Cited by 8 publications

References 39 publications

Staphylococcus aureus Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5

Staphylococcus aureus Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5

Blocking peptides and molecular mimicry as treatment for kidney disease

Peptide Ligands Selected with CD4-Induced Epitopes on Native Dualtropic HIV-1 Envelope Proteins Mimic Extracellular Coreceptor Domains and Bind to HIV-1 gp120 Independently of Coreceptor Usage

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