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At least 19 recordsLinked to original sources
PubMed2001

Male fertility defects in mice lacking the serine protease inhibitor protease nexin-1.

Understanding infertility and sterility requires knowledge of the molecular mechanisms underlying sexual reproduction. We have found that male mice deficient for the gene encoding the protease inhibitor protease nexin-1 (PN-1) show a marked impairment in fertility from the onset of sexual maturity. Absence of PN-1 results in altered semen protein composition, which leads to inadequate semen coagulation and deficient vaginal plug formation upon copulation. Progressive morphological changes of the seminal vesicles also are observed. Consistent with these findings, abnormal PN-1 expression was found in the semen of men displaying seminal dysfunction. The data demonstrate that the level of extracellular proteolytic activity is a critical element in controlling male fertility.

Amyloid beta-Protein Precursor↗
PubMed2006

A comparison of three highly active antiretroviral treatment strategies consisting of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long-term randomised trial.

BACKGROUND: Long-term data from randomised trials on the consequences of treatment with a protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or both are lacking. Here, we report results from the FIRST trial, which compared initial treatment strategies for clinical, immunological, and virological outcomes. METHODS: Between 1999 and 2002, 1397 antiretroviral-treatment-naive patients, presenting at 18 clinical trial units with 80 research sites in the USA, were randomly assigned in a ratio of 1:1:1 to a protease inhibitor (PI) strategy (PI plus nucleoside reverse transcriptase inhibitor [NRTI]; n=470), a non-nucleoside reverse transcriptase inhibitor (NNRTI) strategy (NNRTI plus NRTI; n=463), or a three-class strategy (PI plus NNRTI plus NRTI; n=464). Primary endpoints were a composite of an AIDS-defining event, death, or CD4 cell count decline to less than 200 cells per mm3 for the PI versus NNRTI comparison, and average change in CD4 cell count at or after 32 months for the three-class versus combined two-class comparison. Analyses were by intention-to-treat. This study is registered ClinicalTrials.gov, number NCT00000922. FINDINGS: 1397 patients were assessed for the composite endpoint. A total of 388 participants developed the composite endpoint, 302 developed AIDS or died, and 188 died. NNRTI versus PI hazard ratios (HRs) for the composite endpoint, for AIDS or death, for death, and for virological failure were 1.02 (95% CI 0.79-1.31), 1.07 (0.80-1.41), 0.95 (0.66-1.37), and 0.66 (0.56-0.78), respectively. 1196 patients were assessed for the three-class versus combined two-class primary endpoint. Mean change in CD4 cell count at or after 32 months was +234 cells per mm3 and +227 cells per mm3 for the three-class and the combined two-class strategies (p=0.62), respectively. HRs (three-class vs combined two-class) for AIDS or death and virological failure were 1.15 (0.91-1.45) and 0.87 (0.75-1.00), respectively. HRs (three-class vs combined two-class) for AIDS or death were similar for participants with baseline CD4 cell counts of 200 cells per mm3 or less and of more than 200 cells per mm3 (p=0.38 for interaction), and for participants with baseline HIV RNA concentrations less than 100 000 copies per mL and 100,000 copies per mL or more (p=0.26 for interaction). Participants assigned the three-class strategy were significantly more likely to discontinue treatment because of toxic effects than were those assigned to the two-class strategies (HR 1.58; p<0.0001). INTERPRETATION: Initial treatment with either an NNRTI-based regimen or a PI-based regimen, but not both together, is a good strategy for long-term antiretroviral management in treatment-naive patients with HIV.

Adult↗
PubMed2006

Virological and immunological outcomes at 3 years after starting antiretroviral therapy with regimens containing non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or both in INITIO: open-label randomised trial.

BACKGROUND: Antiretroviral therapy has greatly reduced HIV mortality and morbidity. However, the best sequence of regimens and implications of initial regimen for long-term therapeutic success are not well defined. METHODS: In INITIO, a large international randomised trial, we compared antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors (didanosine+stavudine) plus either a non-nucleoside reverse transcriptase inhibitor (efavirenz, EFV) or a protease inhibitor (nelfinavir, NFV), or both (EFV/NFV), in patients with HIV-1 infection who had not previously received antiretroviral drugs. Primary outcomes were proportion with undetectable HIV RNA in plasma, and change in CD4 count from baseline at 3 years. Analyses were by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN44582462. FINDINGS: We followed up 911 participants (297 EFV, 311 NFV, 303 EFV/NFV). At 3 years, the proportion with HIV RNA less than 50 copies per mL was highest in the EFV group (188 [74%] EFV, 162 [62%] NFV, 155 [62%] EFV/NFV; p=0.004). Mean (95% CI) increases in CD4 count were 316x10(6) cells per L (288-343) for EFV, 289x10(6) cells per L (262-316) for NFV, and 274x10(6) cells per L (231-291) for EFV/NFV (p=0.1). Fewer participants in the EFV group than in the other groups stopped adequate antiretroviral therapy for more than 30 days (p=0.005). Participants in the EFV/NFV group had shorter time to stopping the initial regimen (p<0.0001) and to a treatment modifying adverse event (p=0.04) than those in the other groups. INTERPRETATION: Starting antiretroviral therapy with a three-drug/two-class regimen including efavirenz was better than starting with regimens including nelfinavir or efavirenz plus nelfinavir in terms of virological suppression and durability of the initial regimen. The shorter time on adequate antiretroviral therapy or to a treatment-modifying adverse event might explain the absence of additional benefit for the four-drug regimen.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Increased expression and localization of a serine protease inhibitor, protease nexin-1 (PN-1), in the ovary and uterus during implantation in rat.

Protease nexin-1 (PN-1) is a serine protease inhibitor (serpin) that inactivates several proteases, including thrombin, urokinase, plasminogen activators (PA), and plasmin. It also plays a role in regulating proteolytic activity generated by PA system. PN-1 is known to be involved in tissue remodeling, cellular invasiveness, matrix degradation, and tumor growth. However, the role of PN-1 in female reproductive tracts, such as the uterus, ovary, and oviduct, during pregnancy is not known. The present study was designed to investigate the changes of PN-1 mRNA level and localization in the tracts during implantation and early pregnancy by using reverse transcription (RT)-polymerase chain reaction (PCR) and in situ hybridization. We found that PN-1 mRNA levels were coordinately regulated during early pregnancy in a stage- and tissue-specific manner, such that an increased expression of PN-1 gene appeared at the time of the implantation period in the uterus and ovary. Both the uterus and ovary synthesized PN-1 mRNA and their maximal PN-1 expression occurred on Day 6.5 postcoitum (p.c.). On 13.5 days of pregnancy, PN-1 level was low in the uterus and ovary. On the other hand, PN-1 mRNA in the oviduct did not show after 6.5 days of pregnancy. It appears that PN-1 mRNA in the uterus and ovary was highly regulated during early pregnancy, which might have an important role in implantation of rat blastocysts. PN-1 was localized in endometrial stromal cells of the uterus and in granulosa cells of the unstimulated primary follicles in the ovary during periimplantation period. Also, PN-1 mRNA expression was higher at implantation period than that at nonimplantation period of pregnancy. In conclusion, PN-1 is expressed in female reproductive tracts and highly regulated during implantation and early pregnancy.

Amyloid beta-Protein Precursor↗
PubMed2001

Novel bifunctional alkaline protease inhibitor: protease inhibitory activity as the biochemical basis of antifungal activity.

An alkaline protease inhibitor (API) from a Streptomyces sp. NCIM 5127 was shown to possess antifungal activity against several phytopathogenic fungi besides its antiproteolytic (anti-feedent) activity [J. V. Vernekar et al. (1999) Biochem. Biophys. Res. Commun. 262, 702-707]. Based on the correlation between antiproteolytic and antifungal activities in several tests such as copurification, heat inactivation, chemical modification, and its binding interaction with the fungal protease, we demonstrate, for the first time, that the dual function of API is a consequence of its ability to inhibit the essential alkaline protease. The parallel enrichment of both the functions during purification together with the heat inactivation of API leading to the concomitant loss of the two activities suggested their presence on a single molecule. Chemical modification of API with NBS resulted in the complete loss of antiproteolytic and antifungal activities, with no gross change in conformation implying the involvement of a Trp residue in the active site of the inhibitor and the presence of a single active site for the two activities. Treatment of API with DTT abolished both the activities although the native structure of API remained virtually unaffected, indicating the catalytic role of the disulfide bonds. Inactivation of API either by active site modification or by conformational changes leads to the concurrent loss of both the antiproteolytic and antifungal activities. Experimental evidences presented here serve to implicate that the antifungal activity of API is a consequence of its protease inhibitory activity.

Amino Acids↗
PubMed2005

Expression of the apoptosis inhibitor protease inhibitor 9 predicts clinical outcome in vaccinated patients with stage III and IV melanoma.

PURPOSE: There have been reports of successful treatment of metastatic melanoma patients with active specific immunotherapy (ASI) using irradiated autologous tumor cell vaccination. It is still unknown why some patients respond and others do not. Tumor cells can evade the immune system, for example through interference with antigen presentation by down-regulation of MHC molecules or expressing proteins interfering with cytotoxic lymphocyte-induced apoptosis like the granzyme B antagonist protease inhibitor 9 (PI-9). EXPERIMENTAL DESIGN: PI-9 expression was detected in melanoma cell lines. To investigated if PI-9 is important in the response to ASI, paraffin-embedded tissues from stage III or IV melanoma patients were stained. RESULTS: PI-9 is expressed in melanoma cells and expression in metastasized melanoma cells is, in this group of patients, an adverse prognostic marker with regard to overall and disease-free survival. Moreover, loss of MHC-1 expression frequently occurs during tumor progression but is not associated with poor clinical outcome. Interestingly, melanoma patients with a favorable clinical outcome after ASI therapy usually have high percentages of activated (granzyme B-positive) tumor-infiltrating lymphocytes at time of first diagnosis and low percentages of activated lymphocytes at time of recurrent tumor. CONCLUSIONS: Expression of PI-9 in metastatic melanoma cells is associated with unfavorable clinical outcome whereas MHC-1 down-regulation is not. Although it cannot be proven that PI-9 expression is directly responsible for failure of immunotherapy, these data suggest that expression of PI-9 could be an important immune escape mechanism and that modulation of this inhibitor may enhance the efficacy of immunotherapy.

Adult↗
PubMed1995

A serine protease inhibitor, protease nexin I, rescues motoneurons from naturally occurring and axotomy-induced cell death.

Protease nexin I (PNI) is a member of the family of serine protease inhibitors (serpins) that have been shown to promote neurite outgrowth in vitro from different neuronal cell types. These include neuroblastoma cells, hippocampal neurons, and sympathetic neurons. Free PNI protein is markedly decreased in various anatomical brain regions, including hippocampus, of patients with Alzheimer disease. Here, we report that PNI rescued spinal motoneurons during the period of naturally occurring (programmed) cell death in the chicken in a dose-dependent fashion. Furthermore, PNI prevented axotomy-induced spinal motoneuron death in the neonatal mouse. The survival effect of PNI on motoneurons during the period of programmed cell death was not associated with increased intramuscular nerve branching. PNI also significantly increased the nuclear size of motoneurons during the period of programmed cell death and prevented axotomy-induced atrophy of surviving motoneurons. These results are consistent with the possible role of PNI as a neurotrophic agent. They also support the idea that serine proteases or, more precisely, the balance of proteases and serpins may be involved in regulating the fate of neuronal cells during development.

Amyloid beta-Protein Precursor↗
PubMed2001

Progressive neuronal and motor dysfunction in mice overexpressing the serine protease inhibitor protease nexin-1 in postmitotic neurons.

Perturbation of the homeostasis between proteases and their inhibitors has been associated with lesion-induced or degenerative neuronal changes. Protease nexin-1 (PN-1), a secreted serine protease inhibitor, is constitutively expressed in distinct neuronal cell populations of the adult CNS. In an earlier study we showed that transgenic mice with ectopic or increased expression of PN-1 in postnatal neurons have altered synaptic transmission. Here these mice are used to examine the impact of an extracellular proteolytic imbalance on long-term neuronal function. These mice develop disturbances in motor behavior from 12 weeks on, with some of the histopathological changes described in early stages of human motor neuron disease, and neurogenic muscle atrophy in old age. In addition, sensorimotor integration, measured by epicranial multichannel recording of sensory evoked potentials, is impaired. Our results suggest that axonal dysfunction rather than cell death underlies these phenotypes. In particular, long projecting neurons, namely cortical layer V pyramidal and spinal motor neurons, show an age-dependent vulnerability to PN-1 overexpression. These mice can serve to study early stages of in vivo neuronal dysfunction not yet associated with cell loss.

Amyloid beta-Protein Precursor↗
PubMed2002

Expression of the granzyme B inhibitor, protease inhibitor 9, by tumor cells in patients with non-Hodgkin and Hodgkin lymphoma: a novel protective mechanism for tumor cells to circumvent the immune system?

In tumor cells, the serine protease granzyme B is the primary mediator of apoptosis induced by cytotoxic T lymphocytes (CTLs)/natural killer (NK) cells. The human intracellular serpin proteinase inhibitor 9 (PI9) is the only known human protein able to inhibit the proteolytic activity of granzyme B. When present in the cytoplasm of T lymphocytes, PI9 is thought to protect CTLs against apoptosis induced by their own misdirected granzyme B. Based on the speculation that tumors may also express PI9 to escape CTL/NK cell surveillance, immunohistochemical studies on the expression of PI9 in various lymphomas were performed. Ninety-two cases of T-cell non-Hodgkin lymphoma (NHL), 75 cases of B-cell NHL, and 57 cases of Hodgkin lymphomas were stained with a PI9-specific monoclonal antibody. In T-cell NHL, highest PI9 expression was found in the extranodal T-cell NHL. In nearly 90% of enteropathy-type T-cell NHLs and 80% of NK/T-cell, nasal-type lymphomas, the majority of the tumor cells expressed PI9. In nodal T-anaplastic large cell lymphomas and peripheral T-cell lymphomas (not otherwise specified), PI9 expression occurred less frequently. In B-cell NHL, PI9 expression was associated with high-grade malignancy; 43% of diffuse large B-cell lymphomas showed PI9(+) tumor cells. Finally, PI9 expression was also found in 10% of Hodgkin lymphomas. This is the first report describing the expression of the granzyme B inhibitor PI9 in human neoplastic cells in vivo. Expression of this inhibitor is yet another mechanism used by tumor cells to escape their elimination by cytotoxic lymphocytes.

Antibodies, Monoclonal↗
PubMed2001

The granzyme B inhibitor, protease inhibitor 9, is mainly expressed by dendritic cells and at immune-privileged sites.

Granzyme B is released from CTLs and NK cells and an important mediator of CTL/NK-induced apoptosis in target cells. The human intracellular serpin proteinase inhibitor (PI)9 is the only human protein able to inhibit the activity of granzyme B. As a first step to elucidate the physiological role of PI9, PI9 protein expression in various human tissues was studied. A mAb directed against human PI9 was developed, which specifically stained PI9-transfected COS-7 cells, and was used for immunohistochemistry. Both in primary lymphoid organs and in inflammatory infiltrates, PI9 was present in different subsets of dendritic cells. Also T-lymphocytes in primary and organ-associated lymphoid tissues were PI9 positive. Endothelial cells of small vessels in most organs tested as well as the endothelial layer of large veins and arteries showed strong PI9 staining. Surprisingly, high PI9 protein expression was also found at immune-privileged sites like the placenta, the testis, the ovary, and the eye. These data fit with the hypothesis that PI9 is expressed at sites where degranulation of CTL or NK cells is potentially deleterious.

Animals↗
PubMed1987

Platelet-activating factor stimulation of rabbit platelets is blocked by serine protease inhibitor (chymotryptic protease inhibitor).

The serine protease inhibitors diethyl p-nitrophenyl phosphate and phenylmethylsulfonyl fluoride (chemical modifiers of serine residue) and N-acetyl-l-tryptophan ethyl ester (competitive inhibitor of chymotryptic protease) inhibited 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (AGEPC; platelet-activating factor)-induced platelet aggregation and secretion. The inhibition was dependent on the preincubation time with the serine protease inhibitor and on the concentration of AGEPC and inhibitor. The IC50 value of diethyl-p-nitrophenyl phosphate, phenylmethylsulfonyl fluoride, and N-acetyl-l-tryptophan ethyl ester towards 5 X 10(-10) M AGEPC in serotonin release was 2.2 X 10(-4), 8.0 X 10(-4), and 5.0 X 10(-4) M, respectively. In experiments where platelets were incubated with these inhibitors and then washed with buffer, the inhibition of AGEPC stimulation was not observed. Prostaglandin H2 analog U46619 (10(-6) to 10(-5) M)- and thrombin (0.1 unit/ml)-induced platelet activation were also blocked by 1 mM diethyl p-nitrophenyl phosphate and 1 mM N-acetyl-l-tryptophan ethyl ester. The binding of AGEPC (1.5 X 10(-11) to 9.4 X 10(-10) M) to platelets and the platelet cyclic AMP level were not affected by diethyl p-nitrophenyl phosphate, phenylmethylsulfonyl fluoride, and N-acetyl-l-tryptophan ethyl ester. However, 1 mM diethyl p-nitrophenyl phosphate and 1 mM N-acetyl-l-tryptophan ethyl ester suppressed 10(-9) M AGEPC-induced breakdown of phosphatidylinositol 4,5-bisphosphate and formation of phosphatidic acid to 10-12 and 39-42%, 40-kDa protein phosphorylation to 4 and 30%, and arachidonic acid release to 17 and 28% of controls, respectively. On the other hand, 5 mM diethyl p-nitrophenyl phosphate did not inhibit diacylglycerol production and arachidonic acid release initiated by 2.5 mM deoxycholate treatment, suggesting that receptor-mediated phospholipase C and phospholipase A2 activation were inhibited by the serine protease inhibitor, but the deoxycholate (physicochemical stimulant)-initiated activation was not. AGEPC-induced 20-kDa protein phosphorylation and the inhibitory action of AGEPC on cyclic AMP accumulation were abolished in the presence of diethyl p-nitrophenyl phosphate and phenylmethylsulfonyl fluoride. However, a tryptic protease inhibitor, 1 mM p-aminobenzamidine and 1 mM benzoyl-l-arginine methyl ester, did not prevent the AGEPC-induced platelet secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Prevention of carcinogenesis by protease inhibitors.

Protease inhibitors are very effective in their ability to suppress carcinogenesis in many different in vivo and in vitro assay systems. One particularly effective protease inhibitor, the soybean-derived Bowman-Birk inhibitor, has been extensively studied in our laboratory. Our results have indicated that Bowman-Birk inhibitor suppresses carcinogenesis 1) induced by several different types of carcinogens, 2) in three different species (mice, rats, and hamsters), 3) in several different tissues/organs [colon, liver, lung, esophagus, and cheek pouch (oral epithelium)], 4) when administered to animals by several different routes (including the diet), 5) involving several different types of tumors (squamous cell carcinomas, adenocarcinomas, angiosarcomas, etc.) and 6) in different cell types [epithelial cells (in the colon, liver, lung, esophagus, and cheek pouch) as well as connective tissue cells (fibroblasts, both in vitro and those in the liver which give rise to angiosarcomas)]. Thus, the remarkable ability of Bowman-Birk inhibitor to serve as an anticarcinogenic agent has been demonstrated in a variety of different carcinogenesis assay systems. Although the mechanism of action of protease inhibitors as anticarcinogenic agents is unknown, many hypotheses have been presented. Our results suggest that anticarcinogenic protease inhibitors are capable of reversing the initiating event in carcinogenesis, presumably by stopping an ongoing process begun by carcinogen exposure. We have observed several effects of protease inhibitors which are thought to be related to their anticarcinogenic activity; these include 1) the ability to affect the expression of certain oncogenes (e.g., c-myc and c-fos) and 2) the ability to affect the levels of certain types of proteolytic activities (e.g., N-t-butoxycarbonyl-Val-Pro-Arg-7-amino-4-methylcoumarin-hydrolyzing activity) which are elevated in carcinogen-exposed tissues. We have also observed other effects of anticarcinogenic protease inhibitors which may be related to carcinogenesis. For example, we have reported that the inhibitors can reduce the carcinogen-induced, elevated levels of gene amplification to nearly normal levels. While all of these effects of protease inhibitors may contribute to the prevention of carcinogenesis, the mechanism by which protease inhibitors prevent cancer cannot be determined with certainty until the mechanisms involved in cancer induction are known. While the mechanism remains unclear, it is clear that protease inhibitors can reverse a number of carcinogen-induced cellular changes which may play important roles in carcinogenesis.

Amino Acid Sequence↗
PubMed1987

Amelioration of immune complex-mediated glomerulonephritis by synthetic protease inhibitors.

Proteases are involved in the pathogenesis of inflammatory diseases by participating in the activation of mediator systems and by producing proteolytic tissue injury. Homeostatic control of inflammation is accomplished in part by physiologic protease inhibitors. The authors investigated the effectiveness of a number of synthetic protease inhibitors in ameliorating the glomerular injury induced by immune complex-mediated glomerulonephritis in mice. Two amidine-type protease inhibitors, bis (5-amidino-2-benzimidazolyl)methane and 1,2-bis (5-amidino-2-benzimidazolyl)ethane, had the greatest effects. They caused a marked reduction in glomerular necrosis (P less than 0.001) but did not affect the amount or site of immune complex localization or leukocyte influx. The inhibition constants of the protease inhibitors against nine purified physiologic proteases were determined. These results were discussed in relation to the effectiveness of the protease inhibitors in reducing glomerular injury. This investigation indicates that the administration of synthetic protease inhibitors can have a beneficial effect on immune-mediated inflammatory injury.

Amidines↗
PubMed1987

Anticarcinogenic action of protease inhibitors.

Protease inhibitors are synthesized in biological systems and play a critical role in controlling a number of diverse physiological functions. They participate in blood clotting and lysis of clots, in growth processes by modulation of proteolytic digestion of proteins and thus availability of amino acids, and in the induction of selective DNA amplification. When incorporated into the diet, protease inhibitors appear to suppress many types of cancer. In vitro, they suppress neoplastic transformation caused by chemical carcinogens, ionizing radiation, and oncogenes. These observations offer the hope that judiciously applied protease inhibitors in small concentrations may prevent a wide range of human cancers. This hope is further supported by epidemiological studies which show that populations consuming relatively large amounts of protease inhibitors have a lower occurrence of cancer. The tasks remaining are to determine the kind and the level of protease inhibitors that are most effective in preventing cancer without also having toxic side effects and to incorporate them into our diet. Perhaps the most encouraging investigations are those using small nontoxic protease inhibitors available in pure form (epsilon-aminocaproic acid, a trypsin plasminogen activator inhibitor, and nicotinamide, a chymotrypsin inhibitor and known vitamin). Both agents have been shown to be preventive agents of cancer in animals and in vitro models. Further studies with natural protease inhibitors may yield even more effective agents which when incorporated into our diet will prevent the development of many types of cancer.

Antineoplastic Agents↗
PubMed1997

Inhibition of cytokine-driven human immunodeficiency virus type 1 replication by protease inhibitor.

Protease inhibitors block virus maturation and prevent the spread of human immunodeficiency virus (HIV)-1 in vitro. HIV-1-positive persons produce higher levels of proinflammatory cytokines that up-regulate HIV-1 replication. For the protease inhibitor to be effective in vivo, it must be able to suppress cytokine-induced HIV-1 replication. The in vitro efficacy of protease inhibitor to block tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-1alpha, and IL-1beta induction of HIV-1 was investigated. While 100 U/mL of the respective cytokines induced a 208- to 22-fold increase in HIV-1 p24 production, addition of protease inhibitor completely inhibited this virus induction. The kinetics indicated a sustained HIV-1 inhibition despite high levels of endogenous TNF-alpha induction. Dilution of protease inhibitor led to increased HIV-1 replication. These results show that while protease inhibitor can prevent cytokine induction of HIV-1 replication, a continual effective dose is required for the inhibition to be sustained.

Cytokines↗
PubMed1996

Second locus involved in human immunodeficiency virus type 1 resistance to protease inhibitors.

Protease inhibitors are potent antiviral agents against human immunodeficiency virus type 1. As with reverse transcriptase inhibitors, however, resistance to protease inhibitors can develop and is attributed to the appearance of mutations in the protease gene. With the substrate analog protease inhibitors BILA 1906 BS and BILA 2185 BS, 350- to 1,500-fold-resistant variants have been selected in vitro and were found not only to contain mutations in the protease gene but also to contain mutations in Gag precursor p1/p6 and/or NC (p7)/p1 cleavage sites. Mutations in cleavage sites give rise to better peptide substrates for the protease in vitro and to improved processing of p15 precursors in drug-resistant clones. Importantly, removal of cleavage site mutations in resistant clones leads to a decrease or even an absence of viral growth, confirming their role in viral fitness. Therefore, these second-locus mutations indicate that cleavage of p15 is a rate-limiting step in polyprotein processing in highly resistant viruses. The functional constraint of p15 processing also suggests that additional selective pressure could further compromise viral fitness and maintain the benefits of antiviral therapies.

Amino Acid Sequence↗
PubMed2004

A genomic analysis of rat proteases and protease inhibitors.

Proteases perform important roles in multiple biological and pathological processes. The availability of the rat genome sequence has facilitated the analysis of the complete protease repertoire or degradome of this model organism. The rat degradome consists of at least 626 proteases and homologs, which are distributed into 24 aspartic, 160 cysteine, 192 metallo, 221 serine, and 29 threonine proteases. This distribution is similar to that of the mouse degradome but is more complex than that of the human degradome composed of 561 proteases and homologs. This increased complexity of rat proteases mainly derives from the expansion of several families, including placental cathepsins, testases, kallikreins, and hematopoietic serine proteases, involved in reproductive or immunological functions. These protease families have also evolved differently in rat and mouse and may contribute to explain some functional differences between these closely related species. Likewise, genomic analysis of rat protease inhibitors has shown some differences with mouse protease inhibitors and the expansion of families of cysteine and serine protease inhibitors in rodents with respect to human. These comparative analyses may provide new views on the functional diversity of proteases and inhibitors and contribute to the development of innovative strategies for treating proteolysis diseases.

Animals↗