Ligand-selective small molecule modulators of the constitutively active vGPCR US28

Amărandi, Roxana-Maria; Lückmann, Michael; Melynis, Motiejus; Jakobsen, Mette H.; Fallah, Zohreh; Spieß, Katja; Hjortø, Gertrud Malene; Pui, Aurel; Frimurer, Thomas M.

doi:10.1016/j.ejmech.2018.05.053

Cited by 10 publications

(6 citation statements)

References 45 publications

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“…We investigated the receptor target(s) of the three non-ELR vCXCL1 GT5 chemokine variants by screening for both agonistic and antagonistic activity on G protein signaling on a panel of all 18 classical human chemokine receptors in an IP accumulation assay ( Fig 4 ). The HCMV-encoded chemokine receptor US28 Δ300 (a C-terminally truncated US28 with increased signaling properties [ 32 ]) was also included. vCXCL1 GT5 was found to activate CXCR2 at ~60% of the maximal activity of CXCL8 and did not activate CXCR1 or any other chemokine receptor ( Fig 4B ), whereas the two N-terminally truncated variants (vCXCL1 GT5 (4–97) and vCXCL1 GT5 (6–97) ) were half as efficacious as the wild-type chemokine on CXCR2 at ~30% (31% and 29%, respectively) the efficacy of the CXCL8 on CXCR2.…”

Section: Resultsmentioning

confidence: 99%

The non-ELR CXC chemokine encoded by human cytomegalovirus UL146 genotype 5 contains a C-terminal β-hairpin and induces neutrophil migration as a selective CXCR2 agonist

et al. 2022

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Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised patients. The UL146 gene exists as 14 diverse genotypes among clinical isolates, which encode 14 different CXC chemokines. One genotype (vCXCL1GT1) is a known agonist for CXCR1 and CXCR2, while two others (vCXCL1GT5 and vCXCL1GT6) lack the ELR motif considered crucial for CXCR1 and CXCR2 binding, thus suggesting another receptor targeting profile. To determine the receptor target for vCXCL1GT5, the chemokine was probed in a G protein signaling assay on all 18 classical human chemokine receptors, where CXCR2 was the only receptor being activated. In addition, vCXCL1GT5 recruited β-arrestin in a BRET-based assay and induced migration in a chemotaxis assay through CXCR2, but not CXCR1. In contrast, vCXCL1GT1 stimulated G protein signaling, recruited β-arrestin and induced migration through both CXCR1 and CXCR2. Both vCXCL1GT1 and vCXCL1GT5 induced equally potent and efficacious migration of neutrophils, and ELR vCXCL1GT4 and non-ELR vCXCL1GT6 activated only CXCR2. In contrast to most human chemokines, the 14 UL146 genotypes have remarkably long C-termini. Comparative modeling using Rosetta showed that each genotype could adopt the classic chemokine core structure, and predicted that the extended C-terminal tail of several genotypes (including vCXCL1GT1, vCXCL1GT4, vCXCL1GT5, and vCXCL1GT6) forms a novel β-hairpin not found in human chemokines. Secondary NMR shift and TALOS+ analysis of vCXCL1GT1 supported the existence of two stable β-strands. C-terminal deletion of vCXCL1GT1 resulted in a non-functional protein and in a shift to solvent exposure for tryptophan residues likely due to destabilization of the chemokine fold. The results demonstrate that non-ELR chemokines can activate CXCR2 and suggest that the UL146 chemokines have unique C-terminal structures that stabilize the chemokine fold. Increased knowledge of the structure and interaction partners of the chemokine variants encoded by UL146 is key to understanding why circulating HCMV strains sustain 14 stable genotypes.

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Section: Resultsmentioning

confidence: 99%

The non-ELR CXC chemokine encoded by human cytomegalovirus UL146 genotype 5 contains a C-terminal β-hairpin and induces neutrophil migration as a selective CXCR2 agonist

et al. 2022

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“…The compound was observed to induce reactivation of latent HCMV infection potentially exposing it to the immune system ( 25 ), however, VUF2274 was originally discovered as a CCR1 antagonist ( 46 ) implying a selectivity issue if used as a drug. In search of potential drug candidates with limited cross-reactivity to endogenous receptors, two subsequent studies surveyed small molecule libraries based on VUF2274 ( 47 , 48 ). Out of the latest study, several compounds emerged with agonistic or inverse agonistic profiles in Gαq-mediated signaling and capable of displacing CCL2 and CCL4, such as compound 56, 64 and 67 ( 48 ).…”

Section: Progress On Drug Targeting Of Us28mentioning

confidence: 99%

“…In search of potential drug candidates with limited cross-reactivity to endogenous receptors, two subsequent studies surveyed small molecule libraries based on VUF2274 ( 47 , 48 ). Out of the latest study, several compounds emerged with agonistic or inverse agonistic profiles in Gαq-mediated signaling and capable of displacing CCL2 and CCL4, such as compound 56, 64 and 67 ( 48 ). These molecules were suggested as scaffolds for further development, but no advances on small molecules targeting US28 have been made since.…”

Section: Progress On Drug Targeting Of Us28mentioning

confidence: 99%

Therapeutic targeting of HCMV-encoded chemokine receptor US28: Progress and challenges

Berg

Rosenkilde

2023

Front. Immunol.

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The pervasive human cytomegalovirus (HCMV) causes significant morbidity in immunocompromised individuals. Treatment using the current standard-of-care (SOC) is limited by severe toxic adverse effects and anti-viral resistance development. Furthermore, they only affect HCMV in its lytic phase, meaning viral disease is not preventable as latent infection cannot be treated and the viral reservoirs persist. The viral chemokine receptor (vCKR) US28 encoded by HCMV has received much attention in recent years. This broad-spectrum receptor has proven to be a desirable target for development of novel therapeutics through exploitation of its ability to internalize and its role in maintaining latency. Importantly, it is expressed on the surface of infected cells during both lytic and latent infection. US28-targeting small molecules, single-domain antibodies, and fusion toxin proteins have been developed for different treatment strategies, e.g. forcing reactivation of latent virus or using internalization of US28 as a toxin shuttle to kill infected cells. These strategies show promise for providing ways to eliminate latent viral reservoirs and prevent HCMV disease in vulnerable patients. Here, we discuss the progress and challenges of targeting US28 to treat HCMV infection and its associated diseases.

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“…Continuing these efforts, investigators have shown that C-terminal truncation of pUS28 (pUS28Δ300) is an effective tool for screening potential inhibitors, as it has reduced membrane recycling, which otherwise camouflages the agonism of some ligands towards pUS28. This mutant was used to discover new scaffolds that could lead to the development of novel pUS28 inhibitors [ 172 , 173 ]. Such studies show promise in the expansion of our arsenal of pUS28 inhibitors that are more effective than VUF2274.…”

Section: Us28 As a Therapeutic Targetmentioning

confidence: 99%

US28: HCMV’s Swiss Army Knife

Krishna

Miller

O’Connor

2018

Viruses

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US28 is one of four G protein coupled receptors (GPCRs) encoded by human cytomegalovirus (HCMV). The US28 protein (pUS28) is a potent signaling molecule that alters a variety of cellular pathways that ultimately alter the host cell environment. This viral GPCR is expressed not only in the context of lytic replication but also during viral latency, highlighting its multifunctional properties. pUS28 is a functional GPCR, and its manipulation of multiple signaling pathways likely impacts HCMV pathogenesis. Herein, we will discuss the impact of pUS28 on both lytic and latent infection, pUS28-mediated signaling and its downstream consequences, and the influence this viral GPCR may have on disease states, including cardiovascular disease and cancer. We will also discuss the potential for and progress towards exploiting pUS28 as a novel therapeutic to combat HCMV.

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Ligand-selective small molecule modulators of the constitutively active vGPCR US28

Cited by 10 publications

References 45 publications

The non-ELR CXC chemokine encoded by human cytomegalovirus UL146 genotype 5 contains a C-terminal β-hairpin and induces neutrophil migration as a selective CXCR2 agonist

The non-ELR CXC chemokine encoded by human cytomegalovirus UL146 genotype 5 contains a C-terminal β-hairpin and induces neutrophil migration as a selective CXCR2 agonist

Therapeutic targeting of HCMV-encoded chemokine receptor US28: Progress and challenges

US28: HCMV’s Swiss Army Knife

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