公开(公告)号：US07700115B2

公开(公告)日：2010-04-20

申请号：US11426301

申请日：2006-06-23

申请人： Michael Ruff ,  Candace Pert

发明人： Michael Ruff ,  Candace Pert

IPC分类号： A61K39/12 ,  A61K39/21 ,  A61K39/00 ,  A61K45/00

CPC分类号： A61K39/21 ,  A61K38/162 ,  A61K39/12 ,  C07K14/005 ,  C07K16/1063 ,  C07K2317/76 ,  C12N2740/15022 ,  C12N2740/16122 ,  C12N2740/16134

摘要： Compositions are disclosed that induce broadly HIV therapeutic and vaccine inducing antibodies against diverse HIV clades and relate to the ability to identify HIV gp120-derived short peptide sequence immunogens and various therapeutic compositions made from the identified peptides which compose CCR5 binding sites. Also disclosed are methods of selecting peptide sequences that are likely candidates for drugs which will offer effective treatment in such areas as Alzheimer's disease, psoriasis, multiple sclerosis and other diseases associated with the human inflammatory cascade as well as related retroviruses such as HTLV-1, the cause of tropical spastic paraparesis.

摘要翻译： 公开了组合物，其广泛地诱导针对不同HIV进化枝的HIV治疗和疫苗诱导抗体，并涉及鉴定HIV gp120衍生的短肽序列免疫原的能力和由构成CCR5结合位点的鉴定的肽制备的各种治疗组合物的能力。 还公开了选择可能候选药物的方法，所述肽序列将在诸如阿尔茨海默氏病，牛皮癣，多发性硬化症和与人类炎性级联相关的其它疾病以及相关的逆转录病毒如HTLV-1， 热带痉挛性截瘫的原因。

公开(公告)号：US10071153B2

公开(公告)日：2018-09-11

申请号：US12688862

申请日：2010-01-16

申请人： Michael Ruff ,  Candace Pert

发明人： Michael Ruff ,  Candace Pert

IPC分类号： A61K39/21 ,  A61K38/16 ,  C07K14/005 ,  C07K16/10 ,  A61K39/12

CPC分类号： A61K39/21 ,  A61K38/162 ,  A61K39/12 ,  C07K14/005 ,  C07K16/1063 ,  C07K2317/76 ,  C12N2740/15022 ,  C12N2740/16122 ,  C12N2740/16134

摘要： Compositions are disclosed that induce broadly HIV therapeutic and vaccine inducing antibodies against diverse HIV clades and relate to the ability to identify HIV gp120-derived short peptide sequence immunogens and various therapeutic compositions made from the identified peptides which compose CCR5 binding sites. Also disclosed are methods of selecting peptide sequences that are likely candidates for drugs which will offer effective treatment in such areas as Alzheimer's disease, psoriasis, multiple sclerosis and other diseases associated with the human inflammatory cascade as well as related retroviruses such as HTLV-1, the cause of tropical spastic paraparesis.

公开(公告)号：US20100184705A1

公开(公告)日：2010-07-22

申请号：US12688862

申请日：2010-01-16

申请人： Michael Ruff ,  Candace Pert

发明人： Michael Ruff ,  Candace Pert

IPC分类号： A61K38/08 ,  C07K7/06 ,  A61P29/00 ,  A61P25/28 ,  A61P17/06 ,  A61P19/02 ,  C12Q1/70

CPC分类号： A61K39/21 ,  A61K38/162 ,  A61K39/12 ,  C07K14/005 ,  C07K16/1063 ,  C07K2317/76 ,  C12N2740/15022 ,  C12N2740/16122 ,  C12N2740/16134

摘要： Compositions are disclosed that induce broadly HIV therapeutic and vaccine inducing antibodies against diverse HIV clades and relate to the ability to identify HIV gp120-derived short peptide sequence immunogens and various therapeutic compositions made from the identified peptides which compose CCR5 binding sites. Also disclosed are methods of selecting peptide sequences that are likely candidates for drugs which will offer effective treatment in such areas as Alzheimer's disease, psoriasis, multiple sclerosis and other diseases associated with the human inflammatory cascade as well as related retroviruses such as HTLV-1, the cause of tropical spastic paraparesis.

摘要翻译： 公开了组合物，其广泛地诱导针对不同HIV进化枝的HIV治疗和疫苗诱导抗体，并涉及鉴定HIV gp120衍生的短肽序列免疫原的能力和由构成CCR5结合位点的鉴定的肽制备的各种治疗组合物的能力。 还公开了选择可能候选药物的方法，所述肽序列将在诸如阿尔茨海默氏病，牛皮癣，多发性硬化症和与人类炎性级联相关的其它疾病以及相关的逆转录病毒如HTLV-1， 热带痉挛性截瘫的原因。

公开(公告)号：US06713445B1

公开(公告)日：2004-03-30

申请号：US09647749

申请日：2001-06-12

申请人： Candace Pert ,  Michael Ruff

发明人： Candace Pert ,  Michael Ruff

IPC分类号： A61K3800

CPC分类号： C07K14/52 ,  A61K38/00

摘要： The HIV-1 envelope protein gp120 is toxic to rodent and human neurons by indirect mechanisms requiring accessory glial cells. Chemokines are known to block gp120 interactions with chemokine receptors on T cells, macrophanges, and microglia, thereby preventing viral infection. Gp120-induced neuronal killing in rat hippocampal cultures was partially or completely prevented by a specific short peptides related to chemokines, specially IKEYFTS (SEQ. ID NO: 2) and LESYT (SEQ. ID NO: 1). These peptides thus have use in the treatment of neurological degenerative diseases having symptoms associated with neuronal cell death.

摘要翻译： HIV-1包膜蛋白gp120通过需要附属胶质细胞的间接机制对啮齿动物和人类神经元有毒性。 已知趋化因子阻断与T细胞，巨噬细胞和小胶质细胞上的趋化因子受体的gp120相互作用，从而防止病毒感染。 通过与趋化因子，特别是IKEYFTS（SEQ ID NO：2）和LESYT（SEQ ID NO：1）相关的特异性短肽部分或完全阻止Gp120诱导的大鼠海马培养物中的神经元杀伤。 因此，这些肽可用于治疗具有与神经元细胞死亡相关的症状的神经退行性疾病。

公开(公告)号：US10130674B2

公开(公告)日：2018-11-20

申请号：US13024324

申请日：2011-02-10

申请人： Candace Pert ,  Michael Ruff

发明人： Candace Pert ,  Michael Ruff

IPC分类号： A61K31/08 ,  A61K38/00 ,  A61K38/08 ,  C07K14/005

摘要： Chemokine signaling is important in neuropathic pain, with microglial cells expressing CCR2 playing a well established key role. DAPTA, a gp120-derived CCR5 entry-inhibitor has been shown to inhibit CCR5-mediated monocyte migration and to attenuate neuroinflammation. We disclose here that as a stabilized analog of DAPTA, the short peptide All D TTNYT (SEQ ID NO:1) exhibits potent antagonism for both CCR2 (IC50 4.2 pM) and CCR5 (IC50 0.18 pM) in monocyte chemotaxis. Oral administration of All D TTNYT (SEQ ID NO:1) (0.05-1 mg/kg) for 7 days fully prevents mechanical allodynia and inhibits the development of thermal hyperalgesia following partial ligation of the sciatic nerve in rats. Administered from day 8 to day 12, All D TTNYT (SEQ ID NO:1) (0.2-1 mg/kg) reverses already established hypersensitivity. All D TTNYT (SEQ ID NO:1) relieves pain hypersensitivity probably through either or both CCR2 and CCR5, since by using genetically deficient animals, we demonstrated that in addition to CCR2, CCR5 is also required for the development of neuropathic pain. Moreover, All D TTNYT (SEQ ID NO:1) is able to reduce spinal microglial activation, monocyte infiltration, and to inhibit inflammatory responses evoked by peripheral nerve injury that cause chronic pain. Our findings suggests that the targeting CCR2/CCR5 should provide greater efficacy than targeting CCR2 or CCR5 alone and dual CCR2/CCR5 antagonist All D TTNYT (SEQ ID NO:1) has the potential for broad clinical use in neuropathic pain treatment.

公开(公告)号：US08178497B2

公开(公告)日：2012-05-15

申请号：US11940147

申请日：2007-11-14

申请人： Michael Ruff ,  Candace Pert

发明人： Michael Ruff ,  Candace Pert

IPC分类号： A61K38/08 ,  A61K38/00

CPC分类号： A61K38/08 ,  A61K38/2278

摘要： Residual HIV-1 replication reemerges after intensive therapy from location or locations in the body called the drug resistant non-plasma viral reservoir. Methods are disclosed of treating HIV by inhibiting or blocking this reemergence with various monomeric therapeutic peptide compositions including monomeric DAPTA prepared in least 80% trifluoroethanol, with vigorous shaking for at least about 24 hours at about 37° C.

摘要翻译： 经过强化治疗后，艾滋病毒1型复制的残留被称为抗药性非血浆病毒储库的身体或位置。 公开了通过用包含至少80％三氟乙醇制备的单体DAPTA的各种单体治疗肽组合物在约37℃剧烈振荡至少约24小时来抑制或阻断该再次出血的方法。

公开(公告)号：US20100216120A1

公开(公告)日：2010-08-26

申请号：US12711070

申请日：2010-02-23

申请人： Candace Pert ,  Michael Ruff ,  Olivier Ducoudret ,  Lokesh Agrawal ,  Noel Baichoo

发明人： Candace Pert ,  Michael Ruff ,  Olivier Ducoudret ,  Lokesh Agrawal ,  Noel Baichoo

IPC分类号： C12Q1/70

CPC分类号： C12Q1/703

摘要： An assay to detect or quantify HIV infectious virus from clinically relevant cellular compartments, or reservoirs, in anti-retrovirally treated patients whose viral levels are low to undetectable is described. The method detects infectious virus in patients whose plasma viral loads are considered to be below the limit of current PCR based detection methods and thereby is more relevant for guiding treatment. A further advantage is that the method allows viral tropism to be directly determined in the presence of specific inhibitors of CCR5 or CXCR4. Drug sensitivity can also be directly determined without the need to laboriously recover patient virus by culture for extended time periods, a method that allows for viral selection or evolution, which is not desirable. Patient cells, like the blood mononuclear cells, or monocytes, are isolated and cultured in the presence of cytokines like CSF-1/M-CSF or GM-CSF. to promote their differentiation. Cells are activated with lectins, mitogenic antibodies, phorbol esters, Toll Receptor stimulation or inducers of NfKb or NFAT, followed by agents that induce viral release, like ATP or stimulation of autophagy with LiCl, spermidine, or rapamycin. A key aspect of the invention relates to the timing of the addition of these agents for optimal viral release. A further aspect of the invention relates to sensitive detection of released virus which can be accomplished by adding so-called reporter cells which are under control of the HIV TAT protein so that upon infection these cells synthesize proteins or enzymes that allow for the measurement of infectious particles.

摘要翻译： 描述了在病毒水平低到不可检测的抗逆转录病毒治疗的患者中检测或定量来自临床相关细胞区室或储库的HIV感染性病毒的测定法。 该方法检测血浆病毒载量低于目前基于PCR检测方法极限的患者中的感染性病毒，从而更有助于指导治疗。 另一个优点是该方法允许在CCR5或CXCR4的特异性抑制剂存在下直接测定病毒向性。 药物敏感性也可以直接确定，而不需要通过培养长时间地费力地恢复患者病毒，这是允许病毒选择或进化的方法，这是不希望的。 在细胞因子如CSF-1 / M-CSF或GM-CSF的存在下分离和培养患者细胞，如血液单核细胞或单核细胞。 促进他们的分化。 细胞被凝集素，有丝分裂抗体，佛波酯，Toll受体刺激或NfKb或NFAT的诱导剂激活，随后是诱导病毒释放的药剂，如ATP或用LiCl，亚精胺或雷帕霉素刺激自噬。 本发明的关键方面涉及添加这些试剂以获得最佳病毒释放的时间。 本发明的另一方面涉及释放的病毒的灵敏检测，其可以通过加入在HIV TAT蛋白质控制下的所谓的报道细胞来实现，使得在感染后，这些细胞合成允许测量感染性的蛋白质或酶 粒子。

公开(公告)号：US20110245180A1

公开(公告)日：2011-10-06

申请号：US13024324

申请日：2011-02-10

申请人： Candace Pert ,  Michael Ruff

发明人： Candace Pert ,  Michael Ruff

IPC分类号： A61K38/02 ,  A61P25/28 ,  A61P27/02 ,  A61P25/00 ,  A61P25/16 ,  A61P35/00 ,  A61P29/00

CPC分类号： A61K38/08 ,  C07K14/005 ,  C12N2740/16122

摘要： Chemokine signaling is important in neuropathic pain, with microglial cells expressing CCR2 playing a well established key role. DAPTA, a gp120-derived CCR5 entry-inhibitor has been shown to inhibit CCR5-mediated monocyte migration and to attenuate neuroinflammation. We disclose here that as a stabilized analog of DAPTA, the short peptide All D TTNYT exhibits potent antagonism for both CCR2 (IC50 4.2 pM) and CCR5 (IC50 0.18 pM) in monocyte chemotaxis. Oral administration of All D TTNYT (0.05-1 mg/kg) for 7 days fully prevents mechanical allodynia and inhibits the development of thermal hyperalgesia following partial ligation of the sciatic nerve in rats. Administered from day 8 to day 12, All D TTNYT (0.2-1 mg/kg) reverses already established hypersensitivity. All D TTNYT relieves pain hypersensitivity probably through either or both CCR2 and CCR5, since by using genetically deficient animals, we demonstrated that in addition to CCR2, CCR5 is also required for the development of neuropathic pain. Moreover, All D TTNYT is able to reduce spinal microglial activation, monocyte infiltration, and to inhibit inflammatory responses evoked by peripheral nerve injury that cause chronic pain. Our findings suggests that the targeting CCR2/CCR5 should provide greater efficacy than targeting CCR2 or CCR5 alone and dual CCR2/CCR5 antagonist All D TTNYT has the potential for broad clinical use in neuropathic pain treatment.

摘要翻译： 趋化因子信号在神经性疼痛中起重要作用，表达CCR2的小胶质细胞发挥了很好的关键作用。 已显示DAPTA，一种来源于gp120的CCR5进入抑制因子，可抑制CCR5介导的单核细胞迁移并减弱神经炎症。 我们在此披露，作为DAPTA的稳定类似物，短肽All D TTNYT在单核细胞趋化性中表现出对CCR2（IC50 4.2pM）和CCR5（IC50 0.18pM）的强拮抗作用。 所有D TTNYT（0.05-1 mg / kg）口服给药7天可完全阻止机械性异常性疼痛，并抑制大鼠坐骨神经部分结扎后的热痛觉过敏发展。 从第8天到第12天，全部D TTNYT（0.2-1 mg / kg）逆转已经建立的超敏反应。 所有D TTNYT可能通过CCR2和CCR5两者或两者缓解疼痛超敏反应，因为通过使用遗传缺陷型动物，我们证明除了CCR2之外，CCR5也是神经性疼痛发展所必需的。 此外，所有D TTNYT能够减少脊髓小胶质细胞活化，单核细胞浸润，并抑制引起慢性疼痛的周围神经损伤引起的炎症反应。 我们的研究结果表明靶向CCR2 / CCR5应该比单独靶向CCR2或CCR5和双CCR2 / CCR5拮抗剂提供更大的功效。所有D TTNYT具有广泛临床应用于神经性疼痛治疗的潜力。

公开(公告)号：US20110152179A1

公开(公告)日：2011-06-23

申请号：US11940147

申请日：2007-11-14

申请人： Michael Ruff ,  Candace Pert

发明人： Michael Ruff ,  Candace Pert

IPC分类号： A61K38/00 ,  A61P31/18

CPC分类号： A61K38/08 ,  A61K38/2278

摘要： Residual HIV-1 replication reemerges after intensive therapy from location or locations in the body called the drug resistant non-plasma viral reservoir. Methods are disclosed of treating HIV by inhibiting or blocking this reemergence with various monomeric therapeutic peptide compositions including monomeric DAPTA prepared in least 80% trifluoroethanol, with vigorous shaking for at least about 24 hours at about 37° C.

摘要翻译： 经过强化治疗后，艾滋病毒1型复制的残留被称为抗药性非血浆病毒储库的身体或位置。 公开了通过用包含至少80％三氟乙醇制备的单体DAPTA的各种单体治疗肽组合物在约37℃剧烈振荡至少约24小时来抑制或阻断该再次出血的方法。

公开(公告)号：US20060292167A1

公开(公告)日：2006-12-28

申请号：US11426301

申请日：2006-06-23

申请人： Michael Ruff ,  Candace Pert

发明人： Michael Ruff ,  Candace Pert

IPC分类号： A61K39/21

CPC分类号： A61K39/21 ,  A61K38/162 ,  A61K39/12 ,  C07K14/005 ,  C07K16/1063 ,  C07K2317/76 ,  C12N2740/15022 ,  C12N2740/16122 ,  C12N2740/16134

摘要： Compositions are disclosed that induce broadly HIV theraputic and vaccine inducing antibodies against diverse HIV clades and relate to the ability to identify HIV gp120-derived short peptide sequence immunogens and various therapeutic compositions made from the identified peptides which compose CCR5 binding sites. Also disclosed are methods of selecting peptide sequences that are likely candidates for drugs which will offer effective treatment in such areas as Alzheimer's disease, psoriasis, multiple sclerosis and other diseases associated with the human inflammatory cascade as well as related retroviruses such as HTLV-1, the cause of tropical spastic paraparesis.

摘要翻译： 公开了组合物，其诱导广泛的HIV治疗和疫苗诱导针对不同HIV进化枝的抗体，并且涉及鉴定HIV gp120衍生的短肽序列免疫原的能力和由构成CCR5结合位点的鉴定的肽制备的各种治疗组合物的能力。 还公开了选择可能候选药物的方法，所述肽序列将在诸如阿尔茨海默氏病，牛皮癣，多发性硬化症和与人类炎性级联相关的其它疾病以及相关的逆转录病毒如HTLV-1， 热带痉挛性截瘫的原因。