Life Sciences & Biotechnology
Title : | Development of non-covalent dual inhibitors against pan-coronavirus MPro and PLPro proteases- Addressing the drug resistance and preparation for the future |
Area of research : | Life Sciences & Biotechnology |
Principal Investigator : | Dr. Anthony Addlagatta, Csir Indian Institute Of Chemical Technology |
Timeline Start Year : | 2024 |
Timeline End Year : | 2027 |
Contact info : | anthony@iict.res.in |
Details
Executive Summary : | The history of human corona viruses (HCoVs) dates back to the 1960s, when 229E and OC43 were confirmed to cause respiratory infections in humans. Despite several reports of their identification, due to low pathogenicity rates they were not considered as dangerous until the emergence of severe acute respiratory syndrome coronavirus in 2002. MERS-CoV and SARS-CoV-2 were identified in 2012 and 2019 respectively which were devastating. The sequence comparison of SARS-CoV-2 with SARS-CoV-1 and MERS-CoV suggest that they share 79% and 50% identity, respectively. Dual inhibitors of main protease (MPro) and papain-like protease (PLPro) not only can prevent viral replication, but also prevent the risk of drug resistance due to mutations in the viral genome. Recently, a high throughput study where a 1.8 million compounds were screened- six molecules were identified as dual inhibitors of MPro and PLPro that showed better antiviral properties. Though both the enzymes are cysteine proteases, their substrate specificities and their active site shapes are different suggesting the design of peptide-based inhibitors can be challenging. Therefore, it is suggested that design of non-peptide small molecules could be a choice to achieve dual inhibition of MPro and PLPro from SARS-CoV-2. Recently, we have developed non-covalent dual inhibitors with 2-chloroquinoline based imine moiety in the nanomolar range against MPro and PLPro from SARS-CoV-2. Also, these molecules are non-cytotoxic against several human cell lines. Preliminary data suggest that these molecules inhibit the SARS-CoV-2 replication at below one micromolar concentration. Detailed antiviral studies are in progress. Biochemical, mutagenesis, mass spectrometric, biophysical, structural and modelling studies have provided the basis for dual inhibition. To the best of our knowledge, ours is first study to develop non-covalent dual inhibitors against MPro and PLPro. This data is yet to be published. Dual inhibitors identified for MPro and PLPro from SARS-CoV-2 may have equal affinity to enzymes from other corona viruses since their active sites are highly conserved in each of their analogue enzymes. Even though corona viruses are hypermutable, the fact that the active sites are conserved among all corona viruses suggest that common inhibitors could be developed against them. Even if there is a chance of mutations, dual inhibitors could hold the ground for longer time and avoid the drug resistance. We propose to explore the lead compounds that we identified as inhibitors of MPro and PLPro from SARS-CoV-2 against homologues proteases from other corona viruses, specifically from SARS-CoV-1 and MERS-CoV. We also propose to optimize the lead molecules by further design and synthesis that will improve their efficacy without compromise on their cytotoxicity. Compounds thus identified will be explored for their antiviral activity against all three viruses in collaborators laboratories. |
Co-PI: | Dr. Srigiridhar Kotamraju Csir Indian Institute Of Chemical Technology,Uppal Road, Tarnaka,Telangana,Hyderabad-500007 |
Total Budget (INR): | 67,99,080 |
Organizations involved
Implementing Agency : | Csir Indian Institute Of Chemical Technology
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Funding Agency : | ANRF/SERB
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