Broad spectrum inhibitors of filoviruses
Inventors
Bowlin, Terry L. • Moir, Donald T. • Chandran, Kartik • Dye, JR., John M. • Williams, John D. • Aron, Zachary D. • Barbor, Jay P. • Lively, Kelly N. • Nash, Peter J. • Mills, Debra M. • Basu, Arnab
Assignees
Albert Einstein College of Medicine • Microbiotix Inc • United States Department of the Army
Publication Number
US-11459308-B2
Publication Date
2022-10-04
Expiration Date
2037-12-05
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Abstract
The present invention is related to the development of therapeutics and prophylactics for the treatment and/or prevention of filovirus infection in humans and other mammals. A new class of small molecules is disclosed that inhibits the interaction of naturally processed (i.e., proteolytically cleaved) filovirus glycoprotein (GPCL) with its host receptor Niemann-Pick C1 (NPC1) protein and thus block infection of host cells by filoviruses. Also disclosed are methods of using the small molecule inhibitors in the treatment/prevention of filovirus infection.
Core Innovation
The invention relates to the discovery and development of novel small molecule inhibitors that block the entry of filoviruses into host cells by targeting the interaction between the proteolytically cleaved filovirus glycoprotein (GPCL) and the host receptor Niemann-Pick C1 (NPC1) protein. The compounds, exemplified notably by a phenyl piperazine (PPZ) series, exhibit potent and broad inhibition of filovirus infection in mammalian cells. These small molecules are disclosed for use in both therapeutic and prophylactic applications against filovirus infection in mammals, including humans.
The problem addressed by the invention is the lack of effective FDA-approved drugs or vaccines against filovirus infections, which include deadly viruses such as Ebola, Sudan, and Marburg viruses. Existing therapeutic approaches, based largely on RNA interference or monoclonal antibodies, are species-specific, costly, difficult to deploy in field conditions, and unproven in human populations. There is an acute unmet need for affordable, broad-spectrum, small molecule therapeutics that can be used to treat or prevent infections caused by different filoviruses, especially during outbreaks.
The core innovation is the identification, isolation, and characterization of this new class of small molecules that specifically disrupt the necessary interaction between NPC1 domain C and GPCL, thereby preventing viral entry and infection. The compounds have been structurally optimized for potency, metabolic stability, selectivity, and pharmacokinetic properties. The compounds are suitable for use in pharmaceutical compositions and methods for treating or preventing infection by any of the principal filoviruses, with demonstrated efficacy in cell culture and animal models.
Claims Coverage
The claims of the patent provide coverage for five distinct molecular scaffolds and corresponding pharmaceutical compositions, and methods of inhibiting filovirus infection using these compounds, as well as specific compounds and their use.
Compounds of Formula I and pharmaceutical compositions thereof
A composition comprising a compound of Formula I, in which the structure is defined by specific permutations for X, Y, A, U, V, Z, R1, R2, R3, R4, R5, R6, and W, covering a class of small molecules that inhibit the interaction between filovirus GPCL and NPC1. The composition may include a pharmaceutically acceptable carrier or excipient, and may be formulated for oral, parenteral, or topical administration.
Compounds of Formula II and pharmaceutical compositions thereof
A composition comprising a compound of Formula II—a specific structural variation of the core inhibitory scaffold—potentially with a pharmaceutically acceptable carrier or excipient, and formulated for oral, parenteral, or topical administration.
Compounds of Formula III and pharmaceutical compositions thereof
A compound of Formula III as disclosed, including variants where a pharmaceutically acceptable carrier or excipient is present, with optional additional antiviral compounds, and formulations suitable for oral, parenteral, or topical administration.
Compounds of Formula IV and pharmaceutical compositions thereof
A compound of Formula IV, as defined structurally in the claims, including pharmaceutical compositions with a pharmaceutically acceptable carrier or excipient, with or without additional antiviral compound, and formulated for oral, parenteral, or topical use.
Compounds of Formula V and pharmaceutical compositions thereof
A compound of Formula V, described by specified substituent groups, including pharmaceutical compositions possibly containing an additional antiviral agent, and formulations for oral, parenteral, or topical administration.
Method of inhibiting filovirus infection in mammals using a compound of Formula I
A method for inhibiting filovirus infection in a mammal, comprising administering to a mammal in need thereof an effective amount of the composition comprising a compound of Formula I. The method is applicable to various filoviruses including Ebola, Sudan, Reston, Bundibugyo, Taï, Marburg, and Ravn viruses. Claim coverage includes administration to humans.
Method of inhibiting filovirus infection in mammals using a compound of Formula II
A method whereby a compound of Formula II is administered to a mammal to inhibit filovirus infection. The claim encompasses the principal filoviruses and formulations for delivery to humans.
Method of inhibiting filovirus infection in mammals using a compound of Formula III
A method of inhibiting filovirus infection by administering a compound of Formula III to a mammal in need thereof—applicable to the key filoviruses and with coverage for compositions formulated for mammalian and human use.
Method of inhibiting filovirus infection in mammals using a compound of Formula IV
A method involving administration of a compound of Formula IV for inhibiting filovirus infection in a mammal, with specified coverage of all principal filoviruses and formulations for both general mammalian and human use.
Method of inhibiting filovirus infection in mammals using a compound of Formula V
A method of administering a compound of Formula V to a mammal to inhibit filovirus infection, covering use with the major filoviruses and formulations for administration to humans.
Specific filovirus inhibitor compounds and their salts
Coverage for individual listed compounds, such as 1-benzhydryl-6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazole and numerous analogs, as well as their pharmaceutically acceptable salts.
The claims broadly protect a novel class of small molecules and their pharmaceutical compositions, defined by specific structural formulas, for inhibiting filovirus infection in mammals, especially humans. The claims encompass methods of therapeutic and prophylactic use, as well as specific example compounds and formulations.
Stated Advantages
The inhibitors provide broad protection against authentic filovirus infection in cell culture and animal models, including Ebola, Sudan, and Marburg viruses.
These small molecule therapeutics are highly attractive for drug development due to their novel mechanism of action targeting the GPCL/NPC1 interaction, a unique molecular target for broad-spectrum anti-filovirus therapy.
Unlike species-specific biologic therapies, these small molecules offer broad-spectrum activity and cost-effective production, potentially useful for rapid deployment in emergencies.
The compounds exhibit low cytotoxicity and high metabolic stability, as well as favorable pharmacokinetic and pharmacodynamic properties in animal studies.
The inhibitors are selective for filoviruses and do not significantly affect arenavirus infection, consistent with their specificity for NPC1, which is not involved in arenavirus entry.
Optimized analogs demonstrate oral and parenteral bioavailability, allowing multiple routes of administration and aiding deployment.
Documented Applications
Treatment and/or prevention of filovirus infections in mammals, particularly humans.
Use in pharmaceutical compositions formulated for oral, parenteral, or topical administration to inhibit filovirus infection.
Treatment or prevention of infection by Ebola virus, Sudan virus, Reston virus, Bundibugyo virus, Taï Forest virus, Marburg virus, or Ravn virus.
Manufacture of a medicament for filovirus infection in mammals.
Combination therapy with one or more known antiviral agents for treatment or prevention of filovirus infections.
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