Several cationic amphiphilic drugs (CADS) have been found to inhibit cell entry of
filoviruses and other enveloped viruses. Structurally unrelated CADs may have antiviral
activity, yet the underlying common mechanism and structure-activity relationship
are incompletely understood. We aimed to understand how widespread antiviral activity
is among CADs and which structural and physicochemical properties are linked to entry
inhibition. We measured inhibition of Marburg virus pseudoparticle (MARVpp) cell entry
by 45 heterogeneous and mostly FDA-approved CADs and cytotoxicity in EA.hy926 cells.
We analyzed correlation of antiviral activity with four chemical properties: pKa,
hydrophobicity (octanol/water partitioning coefficient; ClogP), molecular weight,
and distance between the basic group and hydrophobic ring structures. Additionally,
we quantified drug-induced phospholipidosis (DIPL) of a CAD subset by flow cytometry.
Structurally similar compounds (derivatives) and those with similar chemical properties
but unrelated structures (analogues) to those of strong inhibitors were obtained by
two in silico similarity search approaches and tested for antiviral activity. Overall,
11 out of 45 (24%) CADs inhibited MARVpp by 40% or more. The strongest antiviral compounds
were dronedarone, triparanol, and quinacrine. Structure-activity relationship studies
revealed highly significant correlations between antiviral activity, hydrophobicity
(ClogP > 4), and DIPL. Moreover, pKa and intramolecular distance between hydrophobic
and hydrophilic moieties correlated with antiviral activity but to a lesser extent.
We also showed that in contrast to analogues, derivatives had antiviral activity similar
to that of the seed compound dronedarone. Overall, one-quarter of CADs inhibit MARVpp
entry in vitro, and antiviral activity of CADs mostly relies on their hydrophobicity
yet is promoted by the individual structure.
