Targeted Redesign of Suramin Analogs for Novel Antimicrobial Lead Development

The
emergence of new viral infections and drug-resistant bacteria
urgently necessitates expedient therapeutic development. Repurposing
and redesign of existing drugs against different targets are one potential
way in which to accelerate this process. Suramin was initially developed
as a successful antiparasitic drug but has also shown promising antiviral
and antibacterial activities. However, due to its high conformational
flexibility and negative charge, suramin is considered quite promiscuous
toward positively charged sites within nucleic acid binding proteins.
Although some suramin analogs have been developed against specific
targets, only limited structure–activity relationship studies
were performed, and virtual screening has yet to be used to identify
more specific inhibitor(s) based on its scaffold. Using available
structures, we investigated suramin’s target diversity, confirming
that suramin preferentially binds to protein pockets that are both
positively charged and enriched in aromatic or leucine residues. Further,
suramin’s high conformational flexibility allows adaptation
to structurally diverse binding surfaces. From this platform, we developed
a framework for structure- and docking-guided elaboration of suramin
analog scaffolds using virtual screening of suramin and heparin analogs
against a panel of diverse therapeutically relevant viral and bacterial
protein targets. Use of this new framework to design potentially specific
suramin analogs is exemplified using the SARS-CoV-2 RNA-dependent
RNA polymerase and nucleocapsid protein, identifying leads that might
inhibit a wide range of coronaviruses. The approach presented here
establishes a computational framework for designing suramin analogs
against different bacterial and viral targets and repurposing existing
drugs for more specific inhibitory activity.