Synthesis of adenine dinucleosides SAM analogs as specific inhibitors of SARS-CoV nsp14 RNA cap guanine-N7-methyltransferase

Abstract

The spreading of new viruses is known to provoke global human health threat. The current COVID-19 pandemic caused by the recently emerged coronavirus SARS-CoV-2 is one significant and unfortunate example of what the world will have to face in the future with emerging viruses in absence of appropriate treatment. The discovery of potent and specific antiviral inhibitors and/or vaccines to fight these massive outbreaks is an urgent research priority. Enzymes involved in the capping pathway of viruses and more specifically RNA N7-or 2 0 O-methyltransferases (MTases) are now admitted as potential targets for antiviral chemotherapy. We designed bisubstrate inhibitors by mimicking the transition state of the 2 0-O-methylation of the cap RNA in order to block viral 2 0-O MTases. This work resulted in the synthesis of 16 adenine dinucleosides with both adenosines connected by various nitrogen-containing linkers. Unexpectedly, all the bisubstrate compounds were barely active against 2 0-O MTases of several flaviviruses or SARS-CoV but surprisingly, seven of them showed efficient and specific inhibition against SARS-CoV N7-MTase (nsp14) in the micromolar to submicromolar range. The most active nsp14 inhibitor identified is as potent as but particularly more specific than the broad-spectrum MTase inhibitor, sinefungin. Molecular docking suggests that the inhibitor binds to a pocket formed by the S-adenosyl methionine (SAM) and cap RNA binding sites, conserved among SARS-CoV nsp14. These dinucleoside SAM analogs will serve as starting points for the development of next inhibitors for SARS-CoV-2 nsp14 N7-MTase.

The Novel Insight of SARS-CoV-2 Molecular Biology and Pathogenesis and Therapeutic Options

“…Three natural and microbial extracts of PF35468, PA48202, and PA48523 products may inhibit SARS-CoVnsp14 (Sun et al, 2014b). One of the opposite approaches to COVID-19 can be to inhibit this protein, which is one of the treatment options based on the adenine dinucleoside SAM analogues (Ahmed-Belkacem et al, 2020).…”

Druggable targets from coronaviruses for designing new antiviral drugs

“… 261 , 262 ([Bi(L5) (H 2 O) (ClO 4 ) 3 ], L5 = Synthetic SARS-CoV 5.0 µM nsP13 Not revealed a 263 Synthetic SARS-CoV 3.0 µM nsP13 Not revealed a 264 Synthetic SARS-CoV 11.0 µM nsP13 Not revealed a 265 Guanine-N 7 -Methyltransferase (also named as N 7 -MTase or nsP14) Synthetic SARS-CoV 0.6 µM nsP14 (PDB: 5C8T) - Trp 385 , Phe 401 , Tyr 420 , Phe 426 , Phe 506 , Cys 387 , Pro 335 , Val 290 , Trp 292 , Ile 332 , Phe 367 , Ala 353 , Val 389 , Asn 386 (H), Arg 310 (H), Gly 333 (H), Ile 338 (H), Lys 336 (H), His 424 (H), and Asp 352 (H). 266 *: Divergent residue labeling due to the difference between the SARS-CoV, SARS-CoV-2, and MERS-CoV proteins’ structures. a : The authors have not performed in silico studies.…”

“… 282 In this context, nucleoside SAM analogs could target nsP14 from both viruses. A potent SARS-CoV nsP14 inhibitor was synthesized by Ahmed-Belkacem et al (2020), 266 in which it demonstrated an IC 50 value of 0.6 µM. Additionally, it was verified that this compound is able to perform seven hydrogen-bonding interactions, with Arg 310 , Gly 333 , Lys 336 , Ile 338 , Asp 352 , Asn 386 , and His 424 .…”

Evaluation of the elemental, nutritional and antioxidant properties of Cov-Pla herbal preparations

“…A number of strategies are being pursued for the discovery of new therapeutics for the disease. These include repurposing of existing drugs (Santos et al, 2020), computer aided drug discovery (Onawole et al, 2020) and de novo synthesis and screening of small molecules against the SARS-CoV-2 virus (Ahmed-Belkacem et al, 2020;Jockusch et al, 2020). Another approach which is fast gaining traction for the discovery of new drugs against this disease is the exploration of plant material for herbal medicines against the disease (Cao et al, 2020;Wang et al, 2020).…”