Modulating nudix homology domain (nhd) with nicotinamide mononucleotide analogs and derivatives of same

Abstract

The invention provides methods of modulating and regulating NHD protein-protein interactions through nicotinamide mononucleotide, analogs and derivatives thereof, such as NAD+. Such modulation may be useful in methods of treating and preventing cancer, aging, cell death, radiation damage, radiation exposure, among others, may improve DNA repair, cell proliferation, cell survival, among others, and may increase the life span of a cell or protect it against certain stresses, among others

1 . A method for recovering from, treating, or preventing cancer in a subject in need thereof comprising administering an effective amount of
 a) nicotinamide mononucleotide, or an analog or derivative thereof;   b) an agent that increases the level of nicotinamide mononucleotide, or an analog or derivative thereof; or   c) both a) and b);   
       to the subject to thereby modulate the activity of a biologically active polypeptide comprising a Nudix homology domain (NHD), or fragment thereof, or a nucleic acid encoding same. 
     
     
         2 . A method for recovering from, treating, or preventing aging or cell death in a subject in need thereof comprising administering an effective amount of
 a) nicotinamide mononucleotide, or an analog or derivative thereof;   b) an agent that increases the level of nicotinamide mononucleotide, or an analog or derivative thereof; or   c) both a) and b);   
       to the subject to thereby modulate the activity of a biologically active polypeptide comprising a Nudix homology domain (NHD), or fragment thereof, or a nucleic acid encoding same. 
     
     
         3 . A method for recovering from, treating, or preventing radiation damage or radiation exposure or in a subject in need thereof comprising administering an effective amount of
 a) nicotinamide mononucleotide, or an analog or derivative thereof;   b) an agent that increases the level of nicotinamide mononucleotide, or an analog or derivative thereof; or   c) both a) and b);   
       to the subject to thereby modulate the activity of a biologically active polypeptide comprising a Nudix homology domain (NHD), or fragment thereof, or a nucleic acid encoding same. 
     
     
         4 . A method for recovering from, treating, or preventing chemotherapy-induced damage or cellular senescence in a subject in need thereof comprising administering an effective amount of
 a) nicotinamide mononucleotide, or an analog or derivative thereof;   b) an agent that increases the level of nicotinamide mononucleotide, or an analog or derivative thereof; or   c) both a) and b);   
       to the subject to thereby modulate the activity of a biologically active polypeptide comprising a Nudix homology domain (NHD), or fragment thereof, or a nucleic acid encoding same. 
     
     
         5 . A method for modulating DNA repair in a subject in need thereof comprising administering an effective amount of
 a) nicotinamide mononucleotide, or an analog or derivative thereof;   b) an agent that increases the level of nicotinamide mononucleotide, or an analog or derivative thereof; or   c) both a) and b);   
       to the subject to thereby modulate the activity of a biologically active polypeptide comprising a Nudix homology domain (NHD), or fragment thereof, or a nucleic acid encoding same. 
     
     
         6 . A method for modulating cell proliferation or cell survival in a subject in need thereof comprising administering an effective amount of
 a) nicotinamide mononucleotide, or an analog or derivative thereof;   b) an agent that increases the level of nicotinamide mononucleotide, or an analog or derivative thereof; or   c) both a) and b);   
       to the subject to thereby modulate the activity of a biologically active polypeptide comprising a Nudix homology domain (NHD), or fragment thereof, or a nucleic acid encoding same. 
     
     
         7 . The method of any of the preceding claims, wherein said biologically active polypeptide comprising a Nudix homology domain (NHD), or fragment thereof, binds nicotinamide dinucleotide, or an analog or derivative thereof. 
     
     
         8 . The method of any of the preceding claims, wherein the nicotinamide mononucleotide, or an analog or derivative thereof is nicotinamide adenine dinucleotide (NAD+). 
     
     
         9 . The method of  claim 7 , wherein said biologically active polypeptide comprising a Nudix homology domain (NHD), or fragment thereof, comprises the NHD domain of a protein from Deleted Breast Cancer 1 (DBC1), or a protein set forth in Table 3. 
     
     
         10 . The method of any of the preceding claims, wherein said biologically active polypeptide comprising a Nudix homology domain (NHD), or fragment thereof, has a defective, deleted, or mutated protein binding region which inhibits interaction with a protein involved in cancer, aging, radiation damage, DNA repair, cell proliferation, or cell survival. 
     
     
         11 . The method of any of the preceding claims, wherein said biologically active polypeptide comprising a Nudix homology domain (NHD), or fragment thereof, has a defective, deleted, or mutated protein binding region which inhibits interaction with a protein involved in regulating of gene expression, cell cycle, or both, wherein said protein comprises a protein set forth in Table 4. 
     
     
         12 . The method of  claim 11 , wherein the protein involved in regulating of gene expression is selected from the group consisting of proteins involved in RNA processing, translation, transcription, RNA splicing, spliceosomal complex, signal transduction, chromatin remodeling, immune response, trafficking, transcriptional regulation, and circadian cycle. 
     
     
         13 . The method of  claim 11 , wherein the protein involved in regulating cell cycle is selected from the group consisting of proteins involved in proliferation, chromosome condensation, chromosome segregation, DNA damage response, DNA replication, metabolism, nuclear trafficking, immune response. 
     
     
         14 . The method of any one of  claims 10 - 13 , wherein said protein is selected from the group consisting of PARP1, HNRPLL, SON, SUGP2, WDR33, THOC5, PUS1, SYMPK, THOC2, SART3, LSM4, PLRG1, SF3B2, SNRNP40, XAB2, ZCCHC8, PRPF8, PRPF4, POLR3B, POLR1A, POLR2D, POLR2A, SUPT5H, SUPT6H, GT3C4, EXOSC7, EIF4H, GTF3C5, MRPS23, SEP15, FKBP5, MRPS34, TPX2, TRIM27, USP7, UBE2K, STAG2, PDS5B, SMC4, PDS5A, NCAPG2, AKAP8, NUMA1, CEP170, POGZ, CTR9, TBLXR1, G3BP1, TLE1, SPIN1, COPS3, TLE3, GPS1, CSNK2A1, PRKDC, MSH3, MSH6, POLA1, TMPO, FEN1, PRIM2, CHTF18, AKAP8L, MLF2, SPATA5, ZMPSTE24, SMARCA2, SIRT1, SMARCA4, ARID1A, SMARCC2, KDM3B, ADNP, HDAC3, VPRBP, LCP1, KPNA3, TOMM40, IPO9, TIMM13, COBRA1, SAFB2, PELP1, TCEB2, CDK9, TROVE2, SRRT, PSPC1, FAM98B, GK, TXNRD1, NADKD1, NDUFS2, PCK2, CISD1, CYC1, and UQCRFS1, or combination thereof. 
     
     
         15 . The method of any one of  claims 10 - 13 , wherein said protein is selected from the group consisting of PARP1, MATR3, SRRT, NOP56, RIP1L1, UPF1, ZC3H14, HNRNPA0, LRPPRC, FARSA, EIF3D, MRPS22, NOP2, DNAJA2, NSUN2, DNAJA3, DDX5, DHX9, SFPQ, PPP1CB, PPP2R1A, BUB3, ILF3, ADAR, ISG15, NUP155, ZFR, ZC3H11A, KPNA4, KPNA1, KPNA3, KPNA6, ZNF326, SKIV2L2, SON, SUGP2, WTAP, PTBP1, PTBP3, CPSF1, RBM4, HNRNPUL2, SF1, SF3B1, PNN, ZCCHC8, SF3B3, CDC5L, PRPF8, SNRNP200, SAFB, PRMT5, WDR77, SUPT16H, SIRT1, SAP18, IKZF1, HCFC1, HDAC3, ZNF281, ZNF318, GIGYF2, RBM14, SAFB2, SPIN1, GTF21, MCM3, AKAP8L, TRIM28, PSMA2, PSME3, PSMB3, p53, USP11, SLC25A6, PFAS, CAD, SLC25A3, PFKL, ACLY, PPHLN1, RBM12B, and FLNA, or combination thereof. 
     
     
         16 . The method of any one of  claims 1 - 6 , wherein the agent is an NAD+ precursor. 
     
     
         17 . The method of  claim 17 , wherein the NAD+ precursor is nicotinamide mononucleotide (NMN) or a salt thereof, or a prodrug thereof, including crystalline and polymorphic form of same. 
     
     
         18 . The method of any one of  claims 1 - 6 , wherein the agent decreases or reduces nicotinamide. 
     
     
         19 . The method of any one of  claims 1 - 6 , wherein the agent increases the level or activity of an enzyme involved in NAD+ biosynthesis, or an enzymatically active fragment thereof, or a nucleic acid encoding an enzyme involved in NAD+ biosynthesis, or an enzymatically active fragment thereof. 
     
     
         20 . The method of  claim 19 , wherein the enzyme is mononucleotide adenylyl transferase (NMNAT) or nicotinamide phosphoribosyl transferase (NAMPT or NAMPRT). 
     
     
         21 . The method of any one of  claims 1 - 6 , further comprising administering an inhibitor that blocks or prevents protein-protein interaction or binding of said biologically active polypeptide comprising a NHD, or fragment thereof, with said protein involved in cancer, aging, radiation damage, DNA repair, cell proliferation, or cell survival. 
     
     
         22 . The method of any one of  claims 16 - 21 , wherein the agent is administered at a dose of between 0.5-5 grams per day. 
     
     
         23 . The method of any one of  claims 16 - 21 , wherein the agent is administered conjointly, prior to, or subsequent to administrating the biologically active polypeptide comprising the NHD, or fragment thereof, or a nucleic acid encoding same. 
     
     
         24 . The method of any of the preceding claims, wherein the agent or the biologically active polypeptide comprising the NHD, or fragment thereof, or a nucleic acid encoding same is administered in a pharmaceutically effective amount. 
     
     
         25 . The method of  claim 24 , wherein the pharmaceutically effective amount is provided as a pharmaceutical composition in combination with a pharmaceutically-acceptable excipient, diluent, or carrier. 
     
     
         26 . The method of any of the preceding claims, wherein the subject is a mammal or non-mammal. 
     
     
         27 . The method of  claim 26 , wherein the subject is a human.