Kinases are a group of therapeutic targets involved in the progression of numerous diseases, including cancer, rheumatoid arthritis, Alzheimer's disease, and viral infections. The majority of approved antiviral agents are inhibitors of virusspecific targets that are encoded by individual viruses. These inhibitors are narrow-spectrum agents that can cause resistance development. Viruses are dependent on host cellular proteins, including kinases, for progression of their life-cycle. Thus, targeting kinases is an important therapeutic approach to discovering broadspectrum antiviral agents. As there are a large number of FDA approved kinase inhibitors for various indications, their repurposing for viral infections is an attractive and time-sparing strategy. Many kinase inhibitors, including baricitinib, ruxolitinib, imatinib, tofacitinib, pacritinib, zanubrutinib, and ibrutinib, are under clinical investigation for COVID-19. Herein, we discuss FDA approved kinase inhibitors, along with a repertoire of clinical/ preclinical stage kinase inhibitors that possess antiviral activity or are useful in the management of viral infections.
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Bryostatins are complex macrolactones isolated from marine organisms Bryozoan Bugula
neritina. They are potent modulators of protein kinase C isozymes (PKCα: ki = 1.3-188 nM), and are
one of the most extensively investigated marine natural products in clinical trials. Although ~21 natural
bryostatins have been isolated, however only bryostatin-1 (1) has received much interest among
medicinal chemists and clinicians. The structure-activity relationship of bryostatins has been well
established, with the identification of key pharmacophoric features important for PKC modulation. The
low natural abundance and the long synthetic route have prompted medicinal chemists to come-up with
simplified analogs. Bryostatin skeleton comprises three pyran rings connected to each other to form a
macrocyclic lactone. The simplest analog 27 contains only one pyran, which is also able to modulate
the PKCα activity; however, the cyclic framework appears to be essential for the desired level of
potency. Another simplified analog 17 ("picolog") exhibited potent and in-vivo efficacy against lymphoma.
Bryostatin-1 (1) has shown an acceptable intravenous pharmacokinetic profile in mice and
displayed promising in-vivo efficacy in mice models of various cancers and Alzheimer's disease.
Bryostatin-1 was investigated in numerous Phase I/II oncology clinical trials; it has shown minimal
effect as a single agent, however, provided encouraging results in combination with other
chemotherapy agents. FDA has granted orphan drug status to bryostatin-1 in combination with
paclitaxel for esophageal cancer. Bryostatin-1 has also received orphan drug status for fragile X
syndrome. Bryostatin-1 was also investigated in clinical studies for Alzheimer's disease and HIV
infection. In a nutshell, the natural as well as synthetic bryostatins have generated a strong hope to
emerge as treatment for cancer along with many other diseases.
The complex and multifaceted nature of Alzheimer’s
disease
has brought about a pressing demand to develop ligands targeting multiple
pathways to combat its outrageous prevalence. Embelin is a major secondary
metabolite of Embelia ribes Burm f.,
one of the oldest herbs in Indian traditional medicine. It is a micromolar
inhibitor of cholinesterases (ChEs) and β-site amyloid precursor
protein cleaving enzyme 1 (BACE-1) with poor absorption, distribution,
metabolism, and excretion (ADME) properties. Herein, we synthesize
a series of embelin–aryl/alkyl amine hybrids to improve its
physicochemical properties and therapeutic potency against targeted
enzymes. The most active derivative, 9j (SB-1448), inhibits
human acetylcholinesterase (hAChE), human butyrylcholinesterase (hBChE),
and human BACE-1 (hBACE-1) with IC50 values of 0.15, 1.6,
and 0.6 μM, respectively. It inhibits both ChEs noncompetitively
with k
i values of 0.21 and 1.3 μM,
respectively. It is orally bioavailable, crosses blood–brain
barrier (BBB), inhibits Aβ self-aggregation, possesses good
ADME properties, and protects neuronal cells from scopolamine-induced
cell death. The oral administration of 9j at 30 mg/kg
attenuates the scopolamine-induced cognitive impairments in C57BL/6J
mice.
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