Cystic Fibrosis 2021). CF is attributed by the mutation in the CFTR protein, a

cAMP-regulated chloride channel, primarily expressed at the secretory epithelia in

the airways, intestine, and other tissues (Rowe and Verkman 2013). These mutations

lead to thick mucus production in lung airways, blocking the air passage, and,

consequently, increased infection risk and repeated inflammation. There are more

than 2000 identified genetic mutations of the CFTR gene in CF patients (Delavan

et al. 2018; Rowe and Verkman 2013). Amongst the identified CFTR mutations,

F508del and G551D mutations are the major mutations found in more than 90% of

CF patients (Delavan et al. 2018). F508del is associated with the impairment of

CFTR folding, compromising the stability at the endoplasmic reticulum, plasma

membrane, and chloride channel gating (Delavan et al. 2018). On the other hand, the

G551D mutation is related to the alteration of channel gating (Rowe and Verkman

2013).

To date, the FDA-approved drug, ivacaftor, targets only 6% of CF patients with

G551D mutation (Delavan et al. 2018). To ease CF condition, it mainly uses

nebulized inhaled therapies. This includes hyperosmolar inhaled therapy such as

hypertonic saline, mucolytic inhaled therapy such as rhDNase, and inhaled antibiotic

therapies such as colistin, tobramycin, and aztreonam if infection or inflammation is

present (Hurt and Bilton 2014). Therefore, the need for a more effective DR

approach is very crucial. Recently, a drug named Bronchitol or more commonly

known by its active ingredient, mannitol, was successfully repositioned for the

treatment of CF (De Boeck et al. 2017). Mannitol was firstly approved in 1964 by

the FDA for multiple reasons, such as the management of cerebral oedema, increased

intracranial pressure, and removing excess water and toxins in kidney failure patients

(De Boeck et al. 2017). Being a diuretic drug, its capability of drawing water

molecules through epithelial aquaporins confers benefits. In the ventilation airways

of CF patients, the drug reduces the thick and sticky mucus, easing its clearance.

Also, Bronchitol powder can be administered using an inhaler, making the drug

administration much easier, tentatively bringing down the treatment cost signifi-

cantly (Hurt and Bilton 2014). In 2020, Bronchitol gained approval by the FDA and

is expected to be available in March 2021 (Chiesi USA, Inc 2020).

5.3.3.3 SARS-CoV-2 Disease

Amidst the rapid progression of SARS-CoV-2 disease (COVID-19), a new yet

effective therapeutic approach is crucial. The time-consuming, laborious, and costly

methods via conventional drug discovery do not cut it. Therefore, a significant

consideration for DR is indispensable. To no surprise, DR involves numerous

computational methods, in which will be discussed in the following context.

For instance, five proteins of SARS-CoV-2 were selected and generated for DR

target via SWISS-MODEL workspace, namely, the 3-chymotrypsin-like protease

(3CLpro), papain-like protease (PLpro), cleavage site, heptad repeat (HR) 1, and

receptor binding domain (RBD) in the S protein (Mahdian et al. 2020). Subse-

quently, the Protein Data Bank (PDB) was used to coordinate with human

angiotensin-converting enzyme (ACE)-2. Following that, 2471 compounds obtained

from the DrugBank database were screened against the cleavage site and RBD in S

5

Genomic Approaches for Drug Repositioning

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