MK-7845 explained

MK-7845 is an experimental antiviral medication being studied as a potential treatment for COVID-19. It is believed to work by inhibiting SARS-CoV-2 main protease (3CL^pro), a crucial enzyme for viral replication.^{[1] [2]}

Mechanism of action

MK-7845 functions as a reversible covalent inhibitor of the SARS-CoV-2 main protease (also known as 3CL^pro or M^pro). This viral protease enzyme is critical for cleaving viral polyproteins into functional viral proteins necessary for viral replication. The unique cleavage site recognized by 3CL^pro features a glutamine residue at the P1 position that is not utilized by human proteases, making it an attractive target for drug development. Unlike other covalent inhibitors that typically utilize an amide group as a glutamine mimic at this position, MK-7845 incorporates a difluorobutyl substituent. Research demonstrates that this modification interacts with the protease's His163 residue, a crucial component for the binding and inhibition of the enzyme.

Research

In vitro studies have demonstrated that MK-7845 exhibits nanomolar potency against a broad spectrum of clinical subvariants of SARS-CoV-2 as well as Middle East respiratory syndrome coronavirus (MERS-CoV). In vivo studies on transgenic mouse models, specifically K18-hACE2 mice (which express human ACE2 receptors) infected with SARS-CoV-2 and K18-hDDP4 mice infected with MERS-CoV, showed that giving MK-7845 by mouth significantly decreased the amount of virus in the lungs, by more than 6 log orders. Additionally, a study also observed that MK-7845 may offer prophylactic protection to mice when administered prior to exposure to the coronaviruses tested.

A process was developed to enable kilogram-scale production of MK-7845 in accordance with good manufacturing practices (GMPs). The production process was optimized to yield drug quantities suitable for safety studies and phase 1 clinical trials.^[3]

Notes and References

1. Shurtleff VW, Layton ME, Parish CA, Perkins JJ, Schreier JD, Wang Y, Adam GC, Alvarez N, Bahmanjah S, Bahnck-Teets CM, Boyce CW, Burlein C, Cabalu TD, Campbell BT, Carroll SS, Chang W, de Lera Ruiz M, Dolgov E, Fay JF, Fox NG, Goh SL, Hartingh TJ, Hurzy DM, Kelly MJ, Klein DJ, Klingler FM, Krishnamurthy H, Kudalkar S, Mayhood TW, McKenna PM, Murray EM, Nahas D, Nawrat CC, Park S, Qian D, Roecker AJ, Sharma V, Shipe WD, Su J, Taggart RV, Truong Q, Wu Y, Zhou X, Zhuang N, Perlin DS, Olsen DB, Howe JA, McCauley JA . Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic . Journal of Medicinal Chemistry . 67 . 5 . 3935–3958 . March 2024 . 38365209 . 10.1021/acs.jmedchem.3c02248.
2. Alvarez N, Adam GC, Howe JA, Sharma V, Zimmerman MD, Dolgov E, Rasheed R, Nizar F, Sahay K, Nelson AM, Park S, Zhou X, Burlein C, Fay JF, Iwamoto DV, Bahnck-Teets CM, Getty KL, Lin Goh S, Salhab I, Smith K, Boyce CW, Cabalu TD, Murgolo N, Fox NG, Mayhood TW, Shurtleff VW, Layton ME, Parish CA, McCauley JA, Olsen DB, Perlin DS . Novel Pan-Coronavirus 3CL Protease Inhibitor MK-7845: Biological and Pharmacological Profiling . Viruses . 16 . 7 . July 2024 . 1158 . 39066320 . 11281459 . 10.3390/v16071158. free .
3. Deprez NR, Hughes JM, Badir SO, Popov S, Andreani T, Bade RS, Hartmanshenn C, Kwok TT, Gauthier Jr DR, Salehi Marzijarani N, Sakhaei Z . Rapid End-Game Process Development and First GMP Production of MK-7845: An Experimental Antiviral Treatment for COVID-19 . Organic Process Research & Development . American Chemical Society (ACS) . 28 . 6 . 2024 . 1083-6160 . 10.1021/acs.oprd.4c00015 . 2157–2167.