A molecular tweezer antagonizes seminal amyloids and HIV infection

Abstract

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.DOI: http://dx.doi.org/10.7554/eLife.05397.001

Semen amyloids participate in spermatozoa selection and clearance

“…Proteostat has been used for detection of a diverse array of amyloid fibrils (Wang et al, 2012; Navarro and Ventura, 2014; Navarro et al, 2016; Taglialegna et al, 2016) including those from human semen (Arnold et al, 2012; Usmani et al, 2014; Lump et al, 2015). Images were acquired on an LSM710 confocal microscope for 20 s with an interval of 1 s using a 20X air objective.…”

Molecular tweezers for lysine and arginine – powerful inhibitors of pathologic protein aggregation

“…40 In most cases, the protein:CLR01 ratio needed for complete inhibition was in the range 1:0.1–1:3. In one case studied so far, the amyloidogenic peptide PrP(106–126), CLR01 was unable to inhibit the aggregation (measured using turbidity), although the morphology of the aggregates in the presence of CLR01 was amorphous rather than fibrillar.…”

“…36 No reduction in viability (XTT assay) was found up to 100 μM in human H1299 non-small cell lung carcinoma cells 82 and up to 500 μM in the HIV reporter cell line TZM-bl. 40 …”

“…In the past decade, we unraveled the potential of molecular tweezers with their unique binding mode to counteract and revert pathologic aggregation of amyloidogenic peptides and proteins, rendering them promising candidates for disease-modifying therapy of major neurological disorders. 36–40 …”

Designer protein disaggregases to counter neurodegenerative disease

“…An alternative strategy is to define ATP-independent protein disaggregases, which may couple binding energy to disaggregation and are operational outside cells. Select small molecules, including CLR01, a lysine- and arginine-specific molecular tweezer, and the green tea polyphenol, EGCG, can safely disaggregate or remodel diverse amyloids [57,58,59••,60]. A human Aβ oligomer- and fibril-specific monoclonal antibody, aducanumab, promotes clearance of Aβ plaques and may retard clinical decline in AD patients and is now in phase 3 trials [61••].…”