Research Projects

Rationale/ gaps in existing knowledge: Molnupiravir and Nirmatrelvir are existing choices of DAA as oral pharmacological agents under EUA by the FDA for COVID-19.1 Structurally, this is a prodrug of beta-D-N4-hydroxycytidine with hydroxylamine functionality.2 Molnupiravir, a ribonucleoside, acts on viral enzyme RdRp, whereas Nirmatrelvir is a covalent inhibitor of SARS-CoV-2 Mpro. DAA is a genuine concern about genotoxicity and viral mutation. Thus, there is a requirement for antivirals, which may not act through viral enzymes to reduce the chances of mutation, and further RNA/DNA incorporation causing genotoxicity. Thus, discovering an oral drug that inhibits through new mechanisms and reduces the possibility of drug resistance and mutagenicity is mandatory. Overall preparedness with oral drug discovery in antiviral research is required to face any challenge related to global health issues or future threats. Novelty: The synthesized and identified anti-COVID lead compound is based on pyridone carboxylic acid, which is unknown, unpublished, novel and a Japanese patent (JP2024-232249. December 27, 2024) has been filed. Significantly, the preliminary lead has potential activity against SARS-CoV-2. The compound showed selective activity in VeroE6/TMPRSS2 cells were compared with the reference drug Nirmatrelvir as a reference compound. Based on preliminary results obtained from Kagoshima University, Japan, under the research collaboration, our potential lead candidate compounds UK-II-50-32 and UK-II-48-31 rapidly disappeared from plasma in mice after intravenous administration. In addition, the oral bioavailability of these compounds was found to be low. Therefore, their inhibitory effect on anti-SARS-CoV-2 replication may not be efficient in a SARS-CoV-2-infected mouse model. Thus, further structural modification is proposed to generate a novel drug-like candidate compound which will pass with the following parameters 1) high nanomolar activity 2) avoid unnecessary metabolism and reduced half-life 3) Safe or no toxicity 4) Acceptable solubility and oral bioavailability, leading to the conversion of the drug candidate. Objectives: To enhance the efficacy of the preliminary discovered lead "pyridone carboxylic acid analogs," we will employ the CADD approach, followed by bioisosteric replacement, synthesis, and antiviral evaluation in comparison with Nirmatrelvir, with the ultimate goal of elucidating the drug's action mechanism. The novelty lies in converting the primarily discovered potential lead (patented molecules: Japanese patent JP2024-232249. date of filing: December 27, 2024)) into an efficacious drug candidate with acceptable pharmacokinetic properties without toxicity through lead optimization, identifying target enzymes for patents, fostering industrial collaboration, and advancing drug development. Methods: An in-silico modeling approach to enhance ADMET, design and selection, chemistry development, synthesis, spectroscopic characterization and antiviral activity evaluation of optimized lead candidate based on preliminary identified pyridone carboxylic acid analogs. To test on VeroE6/TMPRSS2 cells against COVID-19, followed by SAR development and target identification, under an established Japanese collaboration to delineate the mechanism of action. Expected outcome: This project aims to develop a pyridone carboxylic acid-based efficacious drug candidate for treating viral infection, including a drug candidate patent and industrial collaboration.