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Page 4 of 11 Marchand-Adam et al. Rare Dis Orphan Drugs J 2023;2:3 https://dx.doi.org/10.20517/rdodj.2022.24

Figure 1. Complex formation between CatK and C4-S. Electrostatic surface distribution of human CatK. Blue and red areas represent
positively and negatively charged surface domains of CatK, respectively (Chimera software). The spots of two C4-S-binding sites
(exosites) (PDB accession codes 3C9E and 4N8W) are marked by dashed circles, away from the active site. The pan inhibitor of
cysteine proteases E-64 locates in the active site of the enzyme. The peptidase is shown in surface representation, while C4-S and E-64
are shown as sticks.

Thus, from the X-ray crystal structure of CatK, numerous efforts have been made to develop potent,
selective and orally deliverable CatK inhibitors. However, all synthetic inhibitors which have been tested in
preclinical or clinical trials so far exclusively target the active site of CatK, thus blocking both its
collagenolytic activity and other peptidase activities such as maturation of thyroid hormones and TGF-β1
hydrolysis. Therefore, blocking its entire active site may cause unwanted side effects [Figure 2]. Accordingly,
Merck & Co had to discontinue their phase III clinical trials for osteoporosis treatment using Odanacatib,
the most promising drug targeting CatK. Compared with other anti-resorptive agents, Odanacatib
effectively limited osteoclast-mediated bone resorption without suppressing remodeling (preservation of
bone formation). However, despite its ability to increase bone mineral density (BMD) and improve bone
strength in the spine and hip in postmenopausal women with osteoporosis, Odanacatib also increases the
[39]
risk of cardiovascular side effects, specifically stroke . For an exhaustive update of preclinical and clinical
trials conducted with CatK inhibitors, see a recent review: . Thus, new pharmacological approaches are
[34]
urgently needed to design novel inhibitors of human CatK to impair its collagenase activity but not other
physiological regulatory proteolytic activities. One possible strategy that has emerged in recent years and
could help overcome the problems associated with on-target toxicity is focusing on finding either exosite or
allosteric inhibitors, such as tanshinones, which are ectosteric inhibitors isolated from the roots and
rhizomes of the Chinese medicinal herb Salvia miltiorrhiza Bunge (Danshen) [40,41] . It should be noted that
inhibition by gene therapy could also limit adverse off-target effects. Indeed, systemic delivery of a bone-
targeting recombinant adeno-associated virus, serotype 9 (rAAV9), which can deliver to osteoclasts an
artificial microRNA (rAAV9.amiR-ctsk), counteracts bone loss and improves bone mechanical properties in
a murine model of postmenopausal and senile osteoporosis .
[42]

LYMPHANGIOLEIOMYOMATOSIS: CLINICAL FEATURES, DIAGNOSIS AND CURRENT
THERAPY
Clinical features
Lymphangioleiomyomatosis (LAM) is a rare multisystemic disorder that belongs to the group of cystic
pulmonary diseases and mainly affects young women. This disease frequently progresses to chronic
respiratory failure. It can occur sporadically or during a genetic disease, tuberous sclerosis (also known as