A molecular tweezer antagonizes seminal amyloids and HIV infection.
Semen is the main vector for HIV transmission and contains amyloid fibrils that enhance viral infection. Available microbicides that target viral components have proven largely ineffective in preventing sexual virus transmission. In this study, we establish that CLR01, a 'molecular tweezer' specific for lysine and arginine residues, inhibits the formation of infectivity-enhancing seminal amyloids and remodels preformed fibrils. Moreover, CLR01 abrogates semen-mediated enhancement of viral infection by preventing the formation of virion-amyloid complexes and by directly disrupting the membrane integrity of HIV and other enveloped viruses. We establish that CLR01 acts by binding to the target lysine and arginine residues rather than by a non-specific, colloidal mechanism. CLR01 counteracts both host factors that may be important for HIV transmission and the pathogen itself. These combined anti-amyloid and antiviral activities make CLR01 a promising topical microbicide for blocking infection by HIV and other sexually transmitted viruses.
Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
Edina
E
Lump
Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.|Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.
Laura M
LM
Castellano
Institute of Organic Chemistry III/Macromolecular Chemistry, Ulm University, Ulm, Germany.
Christoph
C
Meier
Physical Chemistry I-Biophysical Chemistry, Department of Chemistry and Chemical Biology, Technical University of Dortmund, Dortmund, Germany.
Janine
J
Seeliger
Physical Chemistry I-Biophysical Chemistry, Department of Chemistry and Chemical Biology, Technical University of Dortmund, Dortmund, Germany.
Nelli
N
Erwin
Physical Chemistry I-Biophysical Chemistry, Department of Chemistry and Chemical Biology, Technical University of Dortmund, Dortmund, Germany.
Benjamin
B
Sperlich
Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
Christina M
CM
Stürzel
Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
Shariq
S
Usmani
Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.|Biology Department, Swarthmore College, Swarthmore, United States.
Rebecca M
RM
Hammond
Institute of Virology, Ulm University Medical Center, Ulm, Germany.
Jens
J
von Einem
Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany.
Gisa
G
Gerold
Institute of Gene Therapy, Ulm University Medical Center, Ulm, Germany.
Florian
F
Kreppel
Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany.
Kenny
K
Bravo-Rodriguez
Institute of Experimental Virology, Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany.
Thomas
T
Pietschmann
Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.
Veronica M
VM
Holmes
Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
David
D
Palesch
Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
Onofrio
O
Zirafi
Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.
Drew
D
Weissman
Department of Chemistry, University of Duisburg-Essen, Essen, Germany.
Andrea
A
Sowislok
Department of Chemistry, University of Duisburg-Essen, Essen, Germany.
Burkhard
B
Wettig
Department of Chemistry, University of Duisburg-Essen, Essen, Germany.
Christian
C
Heid
Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.|Ulm-Peptide Pharmaceuticals, Ulm University, Ulm, Germany.
Frank
F
Kirchhoff
Institute of Organic Chemistry III/Macromolecular Chemistry, Ulm University, Ulm, Germany.|Ulm-Peptide Pharmaceuticals, Ulm University, Ulm, Germany.
Tanja
T
Weil
Institute of Organic Chemistry, University of Duisburg-Essen, Essen, Germany.
Frank-Gerrit
FG
Klärner
Department of Chemistry, University of Duisburg-Essen, Essen, Germany.
Thomas
T
Schrader
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.|Brain Research Institute, University of California at Los Angeles, Los Angeles, Los Angeles, United States.|Molecular Biology Institute, University of California, Los Angeles, United States.
Gal
G
Bitan
Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany.
Elsa
E
Sanchez-Garcia
Physical Chemistry I-Biophysical Chemistry, Department of Chemistry and Chemical Biology, Technical University of Dortmund, Dortmund, Germany.
Roland
R
Winter
Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.|Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.
James
J
Shorter
Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.|Ulm-Peptide Pharmaceuticals, Ulm University, Ulm, Germany.
Jan
J
Münch
D000682:Amyloid / Q000037:antagonists & inhibitors*; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000963:Antimetabolites / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D018562:Disease Transmission, Infectious / Q000517:prevention & control; D015658:HIV Infections / Q000517:prevention & control / Q000635:transmission; D006801:Humans; D008297:Male; D010755:Organophosphates / Q000494:pharmacology*; D012661:Semen / Q000737:chemistry / Q000187:drug effects* / Q000821:virology
D000682:Amyloid; D019380:Anti-HIV Agents; D000963:Antimetabolites; D001952:Bridged-Ring Compounds; C583031:CLR01 compound; D010755:Organophosphates
HIV; amyloid; biochemistry; biophysics; human; molecular tweezer; structural biology; viruses