CXCR4-targeting nanobodies differentially inhibit CXCR4 function and HIV entry
Anneleen Van Hout1, Alex Klarenbeek2, Vladimir Bobkov2
1Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
Biochemical Pharmacology
|October 21, 2018
Summary
New nanobodies targeting the CXCR4 receptor show promise for treating HIV. One nanobody, VUN402, selectively inhibits HIV-1 entry while minimizing disruption to normal cell functions, offering a potential new therapeutic strategy.
Area of Science:
- Immunology
- Virology
- Biotechnology
Background:
- The chemokine receptor CXCR4 and its ligand CXCL12 play roles in various diseases, including cancer.
- CXCR4 is crucial for HIV entry into host cells, making it a therapeutic target.
- Existing CXCR4 inhibitors face challenges due to side effects and poor pharmacokinetics.
Purpose of the Study:
- To identify CXCR4-targeting nanobodies with preferential anti-HIV activity.
- To develop nanobodies that minimize interference with other CXCR4-related cellular functions.
- To explore the potential of nanobodies as selective anti-HIV agents.
Main Methods:
- Evaluation of nanobody activity against HIV-1 infection and CXCR4 signaling pathways.
- Assessment of inhibition of CXCL12 binding, calcium mobilization, and cell morphology changes.
- In-depth biological evaluation of selected nanobodies (VUN400, VUN401, VUN402) against various HIV strains.
Main Results:
- All tested nanobodies inhibited CXCL12 binding and calcium mobilization.
- Anti-HIV activity did not consistently correlate with modulation of CXCR4 signaling.
- Nanobody VUN402 showed potent anti-HIV activity while minimally affecting CXCR4 internalization and chemotaxis.
- Distinct epitopes on CXCR4 were recognized by the different nanobodies, explaining varied activity profiles.
Conclusions:
- CXCR4-targeting nanobodies offer a promising approach for selective HIV inhibition.
- Functional separation exists between anti-HIV activity and modulation of CXCR4 signaling.
- Nanobody VUN402 is a potential lead candidate for developing selective and potent anti-HIV therapeutics.
Related Concept Videos
00:46Feedback Inhibition
57.1K
Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
57.1K
01:30Enzyme Inhibition
92.4K
Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
92.4K
02:34Inhibition of Cdk Activity
6.0K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
6.0K
02:45Functional Groups
88.6K
Functional groups are a group of atoms with characteristic properties, which when linked to the carbon skeleton of a molecule, alter the properties of that molecule. For example, the presence of certain functional groups on a molecule will make them hydrophilic, whereas others will make them hydrophobic. These functional groups are an indispensable part of organic chemistry and important components of biological molecules, such as carbohydrates, proteins, lipids, and nucleic acids. Each...
88.6K
01:25Implicit Differentiation
53
In classical mechanics, motion is often described through relationships between spatial coordinates and time. A car moving along a straight highway with constant acceleration serves as a simple case where velocity is an explicit function of time. This scenario results in a linear equation, enabling straightforward analysis using basic differentiation techniques.In contrast, a satellite in circular orbit follows a path defined by an implicit function. The position of the satellite is constrained...
53
01:28Logarithmic Differentiation
59
When a car’s weight and driving forces act on a tire, they impose an external load on the rubber material. This load is resisted internally by forces distributed throughout the tire structure, which are defined as stress. The resulting deformation of the rubber due to this stress is quantified as strain. The relationship between stress and strain governs how the tire deforms under load and is central to understanding its mechanical response during operation.Rubber exhibits a nonlinear...
59