Jan Münch, Ph.D. Ulm University, Germany

Jan Münch is a professor at the Institute of Molecular Virology at Ulm University, Germany. He studied biology and did his graduate studies at the Friedrich Alexander University in Erlangen-Nuremberg on the pathogenesis of HIV. His current research focuses on the isolation and characterization of novel antiviral peptides from body fluids and tissues, along with their evaluation as drug leads or application as biomarker or nanomaterials. He holds several patents and is cofounder of ViroPharmaceuticals, a biotech company focusing on the development of viral anchoring inhibitors. Dr. Münch’s group identified amyloid fibrils in human semen that enhance HIV infection, a seminal discovery that offers novel opportunities to block sexual transmission of the AIDS virus.

The molecular tweezer CLR01 counteracts semen amyloids and inhibits HIV infection

Human semen contains amyloid fibrils, which form by self-assembly of protein fragments produced through enzymatic cleavage of the abundant proteins prostatic acid phosphatase (PAP) and semenogelin (SEM) 1 and 2. These fibrils, for example those composed of the fragment PAP248-286 (termed SEVI, an acronym of Semen-derived Enhancer of Virus Infection), boost viral infection because they are positively charged, and therefore can bridge the electrostatic repulsion between negatively charged viral and cellular membranes (Arnold et al., 2012; Münch et al., 2007; Roan et al., 2011). Counteracting the viral enhancing activity of amyloid in semen is a promising strategy to reduce sexual HIV transmission rates. In our recent publication (Lump, et al. “A molecular tweezer antagonizes seminal amyloids and HIV infection.” eLife, 2015) we demonstrated that the molecular tweezer CLR01 (see figure 1A) specifically binds lysine residues which are highly abundant in amyloidogenic seminal peptides.

We found that CLR01 not only inhibited the fibrillization of the PAP and SEM peptides but also effectively disaggregated pre-formed fibrils. By binding to amyloids, CLR01 neutralized their positive surface charge, which abrogated their ability to sequester virions (Figure 1 C). Interestingly, CLR01 not only impeded the infectivity enhancement mediated by seminal amyloids, but also directly decreased HIV infection. We found that the tweezer selectively destroyed the membrane of HIV particles, resulting in non-infectious virions! CLR01 also inactivated other human pathogenic enveloped viruses, such as Human Cytomegalo Virus, Herpes Simplex Virus type 2, and Hepatitis C Virus without being cytotoxic itself. Thanks to its dual mode of action (Figure 1B) and no apparent side effects, CLR01 is a promising microbicide candidate for preventing sexual transmission of enveloped viral pathogens.
Figure 1: CLR01 acts as a dual-function inhibitor of viral infection. A: Chemical structure of CLR01; B: Schematic overview of the anti-amyloid and antiviral effects of CLR01; C: Confocal microscopy analysis of SEVI fibrils (stained with Proteostat dye) pre-treated with phosphate-buffered saline, CLR01, or CLR03* and incubated with MLV Gag-YFP particles. *CLR03: Tweezer derivative with similar negative charge as CLR01 but lacking hydrophobic sidewalls; used as negative control.