ANTIVIRAL DRUG DISCOVERY TARGETING CORONAVIRUS ENTRY: USAMBARENSINE AS A HIT COMPOUND

RNA viruses represent a persistent threat to global public health due to their
genetic plasticity, zoonotic origins, and capacity for rapid global dissemination.
The repeated emergence of epidemics and pandemics, together with the
limited availability of effective antiviral therapies, highlights the need for
continued antiviral drug discovery. In this context, natural products remain a
historically validated yet underexplored source of antiviral agents.
This thesis investigates the antiviral potential of a bis-indole alkaloid derived
from Strychnos usambarensis against medically relevant RNA viruses. Using a
bio-guided fractionation approach, usambarensine was identified as the
compound responsible for the observed antiviral activity. Antiviral screening
against representative RNA viruses revealed selective, family-level activity
against pathogenic coronaviruses, including SARS-CoV-2, SARS-CoV-1 and
MERS-CoV, while limited or no activity was observed against unrelated viral
families.
Mechanistic investigations indicate that usambarensine disrupts early stages of
viral entry. The data are most consistent with inhibition at the membrane fusion
step via the cathepsin-dependent endosomal pathway, with Cathepsin L
emerging as a plausible molecular target. Although further biochemical and in
vivo validation is required, this work provides the first evidence of antiviral
activity associated with usambarensine and positions it as a promising hit
scaffold for the development of family-specific antivirals.