Oseltamivir (Tamiflu) as a Candidate for SARS-CoV-2 Antiviral Drug

Antiviral drugs are essential for control of initial influenza outbreaks caused by a new virus. The principal target for these drugs is a virus surface glycoprotein, neuraminidase, which facilitates the release of the nascent virus and thus the spread of infection. Creative Biolabs has established excellent platforms for drug development. We provide a variety of antiviral drugs development services to meet the diverse needs of our customers.

Antiviral Drug: Oseltamivir (Tamiflu)

Oseltamivir has shown efficacy in the treatment and prevention of naturally acquired influenza virus infection. Oseltamivir was developed based on two key findings. Firstly, the transition-state analog 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA) was known to be a weak inhibitor of the neuraminidase. Secondly, the structure of the sialic acid substrate in complex with the enzyme active site revealed an empty negatively charged pocket in the region of the C4 on the sugar ring. This suggested that substitution of the C4-OH with a larger basic residue might lead to higher affinity binding. A single substitution of the C4-OH with a 4-guanidino group enhanced binding more than 10,000-fold over DANA.

Based on DANA, oseltamivir has a cyclohexene ring with two substitutions compared with DANA. It has a C4 amino group and a bulky hydrophobic pentyl ether side chain. It is administered as the prodrug oseltamivir phosphate and converted by hepatic esterases to the active compound oseltamivir carboxylate. Oseltamivir is taken orally twice daily, with a dose of 75 mg for adults. The levels of oseltamivir in plasma are estimated to be in the range from 400 to 1200 nM and in saliva to be <5% of plasma levels. Thus, levels in the upper respiratory tract may be significantly lower than 100 nM.

Fig.1 The relationship between oseltamivir and some of the amino acids in the neuraminidase active site.

Services

Rational drug design utilizing available crystal structures of sialic acid analogues bound to the active site of neuraminidase has led to the discovery of a series of potent neuraminidase inhibitors. At Creative Biolabs, based on the amount of NAIs synthesized and the progress in computational chemistry, we have derived optimized quantitative structure-activity relationship (QSAR) models with the purpose of proposing a presumable model for identifying effective inhibitors and designing new compounds. The newly disclosed structural information of the SARS-CoV-2 viruses has established a solid structural basis for structure-based drug design (SBDD) for new-generation drugs. We can provide the SBDD methods as well as other drug development services for the development of new inhibitors for SARS-CoV-2 treatment.

Creative Biolabs is one of the world’s leading service providers for antiviral drugs development. Our state-of-the-art portfolio of technologies enables us to provide you with outstanding support. If you are interested in our services, please contact us for more details.

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