Therapeutic potential for clomiphene, a selective estrogen receptor modulator, in the treatment of COVID‐19

A novel coronavirus disease 2019 (COVID-19) outbreak is a global
concern that has immeasurably impacted mankind's life. At present,
there is no approved therapeutics available to treat this infection and
only the symptomatic management is the base of clinical treatment [1].
Since, the drug development is a time-consuming process, repurposing
the use of an old drug with low adverse effects to treat new infection
could be a reasonable strategy to reduce the massive health and economic
burden of the COVID-19 pandemic. The classical method to develop
an antiviral agent is based on drugs affecting the functions of viral
proteins that play essential role in the viral life cycles [2]. Clomiphene
is a non‐steroidal triphenylethylene derivative belongs to a group of
drugs known as selective estrogen receptor modulators (SERMs) which
exerts both estrogenic agonist and estrogenic antagonist effects. This
drug is used to treat female infertility due to anovulation. Furthermore,
clomiphene is an efficient drug for reversing the impotence in men with
hypogonadism due to low testosterone secretion [3]. Previous studies
have shown that clomiphene has antiviral effects against Ebola virus.
Screening studies for drug repurposing as antivirals indicated that the
antiviral effect of clomiphene is related to cell-based mechanisms independent
to the classical estrogen signaling pathway. In fact, this drug
would interfere with a late stage of Ebola virus entry into target cells,
likely affecting the triggering of fusion of the viral envelope with the
endosomal limiting membrane. This drug showed EC50 values of 11
and 3.8 μM against the two strains EBOV-95 and EBOV-76, respectively,
and a 90% of survival benefit for infected mice [4]. SARS-COV-2 is a
lipid-enveloped virus encounter the endosomal/lysosomal host compartment
in a critical step of infection [5]. Niemann-Pick type C (NP-C)
disease is a rare neurodegenerative disease caused by de