Broadly-neutralizing antibodies (bnAbs) against the Env glycoprotein guide the rational development of vaccines and therapeutic agents to prevent or treat HIV-1 infection. In addition, bnAb-derived binding fragments are instrumental for the study of the structure-function relationships of the conformationally dynamic Env complex. Here, we demonstrate that the anti-viral activity of bnAbs against the Membrane-Proximal External Region of the Env glycoprotein can be enhanced via single-site modification of membrane-interacting Ab areas with synthetic aromatic compounds. Potency enhancement in cell-entry inhibition and standard neutralization assays correlated with an increase in affinity for the native antigen in virions and did not compromise neutralization breadth. Thus, we have established an optimization procedure with the potential of improving functionality of Abs that bind immunotherapeutic targets at membrane surfaces.